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Globally, ocean dumping of chemical waste is a common method of disposal and relies on the assumption that dilution, diffusion, and dispersion at ocean scales will mitigate human exposure and ecosystem impacts. In southern California, extensive dumping of agrochemical waste, particularly chlorinated hydrocarbon contaminants such as DDT, via sewage outfalls and permitted offshore barging occurred for most of the last century. This study compiled a database of existing sediment and fish DDT measurements to examine how this unique legacy of regional ocean disposal translates into the contemporary contamination of the coastal ocean. We used spatiotemporal modeling to derive continuous estimates of sediment DDT contamination and show that the spatial signature of disposal (i.e., high loadings near historic dumping sites) is highly conserved in sediments. Moreover, we demonstrate that the proximity of fish to areas of high sediment loadings explained over half of the variation in fish DDT concentrations. The relationship between sediment and fish contamination was mediated by ecological predictors (e.g., species, trophic ecology, habitat use), and the relative influence of each predictor was context-dependent, with habitat exhibiting greater importance in heavily contaminated areas. Thus, despite more than half a century since the cessation of industrial dumping in the region, local ecosystem contamination continues to mirror the spatial legacy of dumping, suggesting that sediment can serve as a robust predictor of fish contamination, and general ecological characteristics offer a predictive framework for unmeasured species or locations., Competing Interests: Competing interests statement:The authors declare no competing interest.

Knowledge of multi-stressor interactions and the potential for tradeoffs among tolerance traits is essential for developing intervention strategies for the conservation and restoration of reef ecosystems in a changing climate. Thermal extremes and acidification are two major co-occurring stresses predicted to limit the recovery of vital Caribbean reef-building corals. Here, we conducted an aquarium-based experiment to quantify the effects of increased water temperatures and p CO 2 individually and in concert on 12 genotypes of the endangered branching coral Acropora cervicornis, currently being reared and outplanted for large-scale coral restoration. Quantification of 12 host, symbiont and holobiont traits throughout the two-month-long experiment showed several synergistic negative effects, where the combined stress treatment often caused a greater reduction in physiological function than the individual stressors alone. However, we found significant genetic variation for most traits and positive trait correlations among treatments indicating an apparent lack of tradeoffs, suggesting that adaptive evolution will not be constrained. Our results suggest that it may be possible to incorporate climate-resistant coral genotypes into restoration and selective breeding programmes, potentially accelerating adaptation.

Long-term experimental investigations of transgenerational plasticity (TGP) and transgenerational acclimatization to global change are sparse in marine invertebrates. Here, we test the effect of ocean warming and acidification over a 25-month period of Echinometra sp. A sea urchins whose parents were acclimatized at ambient or one of two near-future (projected mid and end of the 21st century) climate scenarios for 18 months. Several parameters linked to performance exhibited strong effects of future ocean conditions at 9 months of age. The Ambient-Ambient group (A-A, both F 0 and F 1 at ambient conditions) was significantly larger (21%) and faster in righting response (31%) compared to other groups. A second set of contrasts revealed near-future scenarios caused significant negative parental carryover effects. Respiration at 9 months was depressed by 59% when parents were from near-future climate conditions, and righting response was slowed by 28%. At 10 months, a selective pathogenic mortality event led to significantly higher survival rates of A-A urchins. Differences in size and respiration measured prior to the mortality were absent after the event, while a negative parental effect on righting (29% reduction) remained. The capacity to spawn at the end of the experiment was higher in individuals with ambient parents (50%) compared to other groups (21%) suggesting persistent parental effects. Obtaining different results at different points in time illustrates the importance of longer term and multigeneration studies to investigate effects of climate change. Given some animals in all groups survived the pathogenic event and that effects on physiology (but not behavior) among groups were eliminated after the mortality, we suggest that similar events could constitute selective sweeps, allowing genetic adaptation. However, given the observed negative parental effects and reduced potential for population replenishment, it remains to be determined if selection would be sufficiently rapid to rescue this species from climate change effects., (© 2021 John Wiley & Sons Ltd.)

Background: The granulocyte-colony stimulating factor (G-CSF) biosimilar filgrastim (Nivestim™) reduces the duration and severity of neutropenia and the frequency of occurrence of febrile neutropenia (FN). Administration of this biosimilar filgrastim and the patient population receiving it at home have not been sufficiently documented in day-to-day medical practice. Insight into home administration may help optimize the management of FN in this setting, potentially at a reduced cost and patient burden vs hospital administration., Materials and Methods: This was a prospective, non-interventional, non-comparative, multisite study involving 171 patients across 29 sites treated with at least one dose of filgrastim. Mean age was 59.3 years, and most patients were female and G-CSF-naïve. The data collected originated from paper-based patient questionnaires and routine documentation by the treating physicians. The primary endpoint was the characterization of patients treated with filgrastim. Secondary endpoints were satisfaction with filgrastim, effectiveness, safety and tolerability, and compliance with prescription., Results: Most patients had solid tumors (95.9%), mainly located in the breast, while 4.7% had malignant hematological disease. Solid tumors were recorded as grade 1 (7.9%), grade 2 (28.0%), grade 3 (45.7%), and grade 4 (3.0%), and the majority of patients classified at TNM Stages I and II. Many patients (71.0%) could self-inject filgrastim and 72.2% found the handling instructions "extremely straightforward and easy to understand" at least once. Nearly all (99.4%) patients found the syringes "easy to use" at least once and 91.7% were willing to continue home administration. The mean patient satisfaction score for home administration was 1.9±0.9, ranging from 1 (very satisfied) to 6 (absolutely dissatisfied). No cases of neutropenia were observed and only one event of FN occurred., Conclusion: Home-based prophylaxis for FN with filgrastim was found to be effective, well tolerated, and well received by patients (ClinicalTrials.gov Identifier: NCT02956967)., Competing Interests: Disclosure B Otremba has nothing to disclose regarding financial relationships or other conflicts of interest; C Hielscher has received honoraria from Pfizer, Roche and Celgene; V Petersen has nothing to disclose regarding financial relationships or other conflicts of interest; C Petrik is an employee of Pfizer Inc and holds stock in Pfizer.

Objectives: To supplement the data collected in randomized clinical trials, the present study in patients with methicillin resistant Staphylococcus aureus (MRSA) pneumonia was conducted to explore the clinical effectiveness of linezolid and vancomycin in a routine clinical setting. Further, the overall costs of the patients' stay in the intensive care unit (ICU) were compared. Methods: This was a retrospective analysis of medical and reimbursement data of adult patients who were treated for MRSA pneumonia with linezolid or vancomycin. Since the subjects were not randomly assigned to treatments, propensity score adjustment was applied to reduce a potential selection bias. Results: In total, 226 patients were included; 95 received linezolid and 131 received vancomycin as initial therapy for MRSA pneumonia. Switches to another antibiotic were observed in 4 patients (4.2%) receiving linezolid and in 23 patients (17.6%) receiving vancomycin (logistic regression analysis; odds ratio linezolid/vancomycin: 0.183; 95% confidence interval [CI]: 0.052-0.647; p<0.01). All-cause in-hospital mortality was also lower in patients receiving linezolid (22 patients [23.2%] vs. 54 patients [41.2%]) (logistic regression analysis; odds ratio linezolid/vancomycin: 0.351; 95% CI: 0.184-0.671; p<0.01). The analysis of the total costs of stay in ICU did not reveal any major differences between the two treatment groups (cost ratio linezolid/vancomycin: 1.29; 95% CI: 0.84-1.98; p=0.24). Conclusions: These findings confirm in a routine clinical setting that linezolid is a valuable therapeutic alternative to vancomycin for the treatment of MRSA pneumonia. However, prospective studies in real-life patient populations are warranted., Competing Interests: MHW and MWP have served as consultants to Pfizer Deutschland GmbH. KB has received lecture fees, research grants, and travel support from Pfizer. SMH has received travel grants from Pfizer. SK, BW, and CP are employees of Pfizer Deutschland GmbH or Pfizer Pharma GmbH, respectively. PS and AG have no potential conflicts of interest to declare.

Given the rapidly changing landscape of antimicrobial resistance, continuous monitoring of antimicrobial susceptibility in clinically relevant bacterial isolates plays an important role in the management of infectious diseases. The Tigecycline Evaluation and Surveillance Trial (TEST) is an ongoing worldwide surveillance programme monitoring the in vitro activity of tigecycline and a panel of representative comparator antibiotics. We report longitudinal susceptibility data on a large set of isolates (n=36,044) from clinically significant bacterial species collected in 25 microbiological laboratories from 2006 to 2014. Trends include a strong increase of carbapenem and levofloxacin resistance in Acinetobacter spp., and smaller increasing rates of ESBL-producing Escherichia coli and vancomycin-resistant enterococci. Across the reporting period, the tigecycline minimum inhibitory concentrations (MICs) at which 50% and 90% of isolates were inhibited remained stable and susceptibility rates were consistently high (93-100%) for all bacterial species., Competing Interests: M.K. is a partner and CEO of Antiinfectives Intelligence GmbH, a research organisation providing services to pharmaceutical companies. B.K.-I. is an employee of Antiinfectives Intelligence GmbH. C.P. is an employee of Pfizer Pharma GmbH. H.S. has received grants or research support from the Bundesministerium für Bildung und Forschung (BMBF), Germany, the German Center for Infection Research (DZIF), Basilea, Novartis and Pfizer, has been a consultant for Astellas, AstraZeneca, Basilea, Cubist, Novartis, Pfizer, Tetraphase, and The Medicines Company, and has received payments for lectures from MSD, Novartis and Pfizer. A.R. has been a consultant for Oxoid/Thermo, MSD, Novartis, InfectoPharm, BAG, Pfizer, Bayer, Siemens, Clinigen, Gilead and bestbion, and has received speakers honoraria from Pfizer. K.B. has received grants or research support from from the Bundesministerium für Bildung und Forschung (BMBF), Germany, the German Center for Infection Research (DZIF), the Bundesministerium für Wirtschaft (BMWi), the European Territorial Cooperation (ETC)/INTERREG, Cepheid and Pfizer as well as lecture, travel and other fees from Cepheid, Cubist Pharmaceuticals, MSD Sharp & Dohme, Novartis Pharma, Oxoid, Pfizer and Siemens Healthcare Diagnostics.

Background: Necrotizing skin and soft tissue infections (NSTI) form a group of aggressive diseases that require radical debridement for infection control. Simultaneously, a high-dose broad spectrum antibiotic regimen needs to be initiated with control of septic complications in the intensive care setting. The aim of this work is to analyze the efficacy and safety of tigecycline in a subpopulation of hospitalized, severely ill surgical NSTI patients who were documented in a large multicenter non-interventional study on tigecycline use in routine clinical practice., Methods: A total of 1,025 patients with severe infections including complicated skin and soft-tissue infections (cSSTI, n=163; 15,9%) were enrolled in a prospective multi-center non-interventional study. Patients were to receive an initial intravenous dose of 100 mg tigecycline, followed by 50 mg twice daily. Prospectively documented parameters included clinical findings, APACHE II score, microbiological and standard laboratory assessments, surgical measures, and clinical outcomes including adverse events., Results: Of 163 patients were treated for cSSTI, with the largest subgroup being NSTI patients (n=50, 30.7% of all cSSTI, mean age 61 y, median APACHE II score 20). Forty-eight NSTI patients (96%) had at least one comorbidity. In 80% of patients, the treatment was started after previous antibiotic treatment had failed and in 34% resistant pathogens were isolated (28% methicillin resistant Staphyloccocus aureus [MRSA], 4% extended-spectrum-beta-lactamase (ESBL)-producing bacteria, and 2% vancomycin-resistant Enterococci (VRE). Tigecycline was administered as a single agent in 32 patients; 17 received combination regimens. Data from one patient were not reported. Rates of clinical cure or improvement with tigecycline treatment were 90.2%. Two patients (4%) had drug related adverse events (one thrombocytopenia and one fever/chills); 10 patients (20%) died., Conclusions: Tigecycline alone or in combination therapy was an effective and safe antibiotic treatment in critically ill and antimicrobially pre-treated patients with NSTI frequently caused by resistant pathogens.

Introduction: Tigecycline is an established treatment option for infections with multiresistant bacteria (MRB). It retains activity against many strains with limited susceptibility to other antibiotics. Efficacy and safety of tigecycline as monotherapy or in combination regimens were investigated in a prospective noninterventional study involving 1,025 severely ill patients in clinical routine at 137 German hospitals., Materials and Methods: Data on the full population have been published; our present analysis focuses on infections caused by MRB. The study population included patients with complicated infections, high disease severity (APACHE II > 15: 65 %) and high MRB prevalence. Most patients had comorbidities, including cardiovascular disease, renal insufficiency, and/or diabetes mellitus. Treatment success was defined as cure/improvement without requirement of further antibiotic therapy., Results: Pathogens isolated from 215 evaluable patients with documented MRB infections included 132 methicillin-resistant Staphylococcus aureus (MRSA), 42 vancomycin-resistant Enterococci (VRE) and 67 Gram-negative extended beta-lactamase (ESBL) producers. Of the MRB subpopulation, 140 patients received tigecycline monotherapy, 75 were treated with combination regimens. High overall clinical success rates were recorded for MRB infections treated with tigecycline alone (94 %) or in combinations (88 %); in detail intraabdominal infections (monotherapy: 90 %; combinations: 93 %), skin/soft tissue infections (93; 100 %), community-acquired pneumonia (100; 100 %), hospital-acquired pneumonia (94,7; 72,7 %), diabetic foot infections (89; 33 %), blood stream infections (100; 100 %) and multiple-site infections (92; 71 %)., Conclusions: Tigecycline achieved high clinical success rates in patients with documented infections involving MRB strains despite high disease severity. These results add to the evidence indicating that tigecycline is a valuable therapeutic option for complicated infections in severely ill patients with a high likelihood of multidrug-resistant pathogen involvement.

Background: Across Europe, methicillin-resistant Staphylococcus aureus (MRSA) is considered to be the primary cause of nosocomial pneumonia (NP). In Germany alone, approximately 14,000 cases of MRSA-associated NP occur annually, which may have a significant impact on health care resource use and associated economic costs. The objective of this study was to investigate the economic impact of linezolid compared with that of vancomycin in the treatment of hospitalized patients with MRSA-confirmed NP in the German health care system., Methods: A 4-week decision tree model incorporated published data and expert opinion on clinical parameters, resource use, and costs (2012 euros) was constructed. The base case first-line treatment duration for patients with MRSA-confirmed NP was 10 days. Treatment success (survival), failure due to lack of efficacy, serious adverse events, and mortality were possible outcomes that could impact costs. Alternate scenarios were analyzed, such as varying treatment duration (7 or 14 days) or treatment switch due to a serious adverse event/treatment failure (at day 5 or 10)., Results: The model calculated total base case inpatient costs of €15,116 for linezolid and €15,239 for vancomycin. The incremental cost-effectiveness ratio favored linezolid (versus vancomycin), with marginally lower costs (by €123) and greater efficacy (+2.7% absolute difference in the proportion of patients successfully treated for MRSA NP). Approximately 85%-87% of the total treatment costs were attributed to hospital stay (primarily in the intensive care unit). Sensitivity analysis yielded similar results., Conclusion: The model results show that linezolid is a cost-effective alternative to vancomycin for MRSA-confirmed NP, largely attributable to the higher clinical response rate of patients treated with linezolid.

This large prospective non-interventional study investigated the effects of tigecycline either as single agent or in combination with other antimicrobial agents in 1,025 patients treated in clinical routine at German hospitals. Sixty-five percent of the patients had APACHE II scores > 15, indicating high overall disease severity. Complicated intra-abdominal infections (cIAI) or complicated skin and skin tissue infections (cSSTI) were the most common indications, with Staphylococcus aureus, Enterococcus faecium and Escherichia coli being the most frequently isolated pathogens. Clinical success was reported at the end of tigecycline therapy in 74.2% of the total population, in 75.4% of the cIAI and in 82.2% of the cSSTI patients. The subpopulation (28.0% of the patients) infected with multidrug-resistant pathogens (methicillin-resistant S. aureus, extended-spectrum β-lactamase producers and vancomycin-resistant enterococci) were treated with similar success rates as the overall population. Tigecycline was generally well tolerated. Drug-related adverse events (AEs) were reported in 7.7% of the total population; 2.5% had serious AEs mostly attributable to inefficacy of therapy or deterioration of the disease. Mortality rates were consistent with the types of infection and severity of illness. There was no indication of excessive mortality associated with tigecycline as had been suggested in previously performed meta-analyses. In this large non-interventional study performed in the clinical routine setting, tigecycline achieved favorable clinical success rates in a patient population with high severity of illness and a high prevalence of multidrug-resistant pathogens and showed a good safety and tolerability profile., (Copyright © 2012 S. Karger AG, Basel.)

Background: After myocardial infarction (MI), extensive remodeling of extracellular matrix contributes to scar formation and preservation of hemodynamic function. On the other hand, adverse and excessive extracellular matrix remodeling leads to fibrosis and impaired function. The present study investigates the role of the small leucine-rich proteoglycan biglycan during cardiac extracellular matrix remodeling and cardiac hemodynamics after MI., Methods and Results: Experimental MI was induced in wild-type (WT) and bgn(-/0) mice by permanent ligation of the left anterior descending coronary artery. Biglycan expression was strongly increased at 3, 7, and 14 days after MI in WT mice. bgn(-/0) mice showed increased mortality rates after MI as a result of frequent left ventricular (LV) ruptures. Furthermore, tensile strength of the LV derived from bgn(-/0) mice 21 days after MI was reduced as measured ex vivo. Collagen matrix organization was severely impaired in bgn(-/0) mice, as shown by birefringence analysis of Sirius red staining and electron microscopy of collagen fibrils. At 21 days after MI, LV hemodynamic parameters were assessed by pressure-volume measurements in vivo to obtain LV end-diastolic pressure, end-diastolic volume, and end-systolic volume. bgn(-/0) mice were characterized by aggravated LV dilation evidenced by increased LV end-diastolic volume (bgn(-/0), 111+/-4.2 microL versus WT, 96+/-4.4 microL; P<0.05) and LV end-diastolic pressure (bgn(-/0), 24+/-2.7 versus WT, 18+/-1.8 mm Hg; P<0.05) and severely impaired LV function (EF, bgn(-/0), 12+/-2% versus WT, 21+/-4%; P<0.05) 21 days after MI., Conclusions: Biglycan is required for stable collagen matrix formation of infarct scars and for preservation of cardiac hemodynamic function.

Objective: After myocardial infarction, angiotensin II (AngII) promotes ventricular remodeling and deposition of extracellular matrix (ECM), e.g., collagen type 1 and 3. Whether AngII regulates the expression of small leucine-rich proteoglycans (SLRP) which are important modulators of collagen fibrillogenesis and are induced after experimental myocardial infarction in rats is not known. The aim of the present study was therefore to analyse in cultured cardiac fibroblasts the expression and secretion of the SLRP biglycan in response to AngII., Methods: Cardiac fibroblasts were isolated from neonatal Wistar Kyoto rats and used in the first passage. Expression of AT(1)- and AT(2)-receptors was verified by RT-PCR. Expression of protoeglycans was analyzed after metabolic labeling with [35S]-sulfate, by SDS-PAGE and Western analysis. In addition, mRNA expression was examined by means of RT-PCR and Northern analysis. The activity of the biglycan promoter was analyzed using three biglycan promoter-luciferase fusion constructs., Results: Biglycan was found to be the predominant proteoglycan produced by neonatal cardiac fibroblasts in vitro. In response to AngII (10(-7) M), secretion of total [35S]-labeled proteoglycans and mRNA of biglycan were increased to 116+/-1.8% and 121+/-11% (n=5, mean+/-S.E.M.) of unstimulated controls, respectively. Biglycan induction in response to AngII was sensitive to Losartan (10(-5) M) and unaffected by PD123177 (10(-6) M), suggesting that the AT(1)-receptor mediates the induction of biglycan. Direct activation of the biglycan promoter downstream of the AT(1)-receptor was excluded by promoter activity assays. Instead, increased release of transforming growth factor beta 1 (TGFbeta1) was detected by ELISA in response to AT(1)-receptor stimulation. Furthermore, neutralising antibodies to TGFbeta1 inhibited biglycan induction in response to AngII., Conclusion: The results indicate that in cardiac fibroblasts AngII via the AT(1)-receptor causes autocrine release of TGFbeta1, which in turn induces biglycan expression and secretion.