Search

This study presents the status and trends of long-term monitoring of the elemental concentrations of zinc (Zn), lead (Pb), and cadmium (Cd) in Hylocomium splendens moss tissue in Cape Krusenstern National Monument (CAKR), Alaska, adjacent to the Red Dog Mine haul road. Spatial patterns of the deposition of these metals were re-assessed for the period from 2006-2017 following an identical study that assessed trends between 2001-2006. In contrast to the widespread and steep declines in Zn and Pb levels throughout most of the study area between 2001-2006, this study showed more mixed results for 2006-2017. At distances within 100 m of the haul road, only Pb decreased between 2006-2017. At distances between 100-5,000 m, however, both Zn and Cd decreased between 2006-2017, with high probabilities of decrease and percent decreases of 11-20% and 46-52% respectively. Lead did not decrease in any of the more distant areas. Following earlier work on lichen species richness in the study area, it appears that 2017 Zn levels are approaching those associated with "background" lichen species richness throughout a relatively large proportion of the study area at least 2,000 m from the haul road and several km from the port site. The findings in this study may be used to plan additional mitigation measures to reduce Zn deposition related to impacts on lichen communities.

Aims: Cardiovascular implantable electronic device (CIED) infection may present as pocket infection or as infective endocarditis (CIED-IE) with vegetation on device leads or heart valves. As aspirin has both anti-inflammatory properties and interferes with platelet aggregation, we hypothesized that ongoing anti-platelet therapy with aspirin may impact clinical and echocardiographic manifestations of CIED infection. Methods and Results: We retrospectively reviewed 415 cases of CIED infection admitted to Mayo Clinic Rochester from 1991 to 2008. Information regarding aspirin use was available in 392 (94.5%) cases and 178 (45%) had received aspirin therapy prior to clinical onset of CIED infection. Although there were no significant differences in pathogen distribution between patients who had received prior aspirin therapy as compared with those who did not, patients on aspirin therapy were less likely to report chills (25% vs. 35%, P = 0.04), sweats (9% vs.18%, P = 0.01), or have peripheral leukocytosis on admission (33% vs. 46%, P = 0.005). Overall, 82 (21%) of 392 patients met the clinical criteria for CIED-IE. Patients on prior aspirin therapy were significantly less likely to have vegetations on CIED leads or heart valves than those who had not received it (15% vs. 26%, P = 0.01). However, despite the lower frequency of CIED-IE in the aspirin group, there was no significant difference (P = 0.97) in the overall survival between the two groups. Conclusion: Aspirin therapy prior to onset of CIED infection was associated with a lower likelihood of vegetation formation on CIED leads or heart valves and associated systemic manifestations of infection. [ABSTRACT FROM AUTHOR]

BACKGROUND: We sought to summarize and critically appraise the literature on the epidemiology of infective endocarditis (IE) in the general population. METHODS: We retrieved population-based IE surveys by searching MEDLINE and EMBASE. Two reviewers independently extracted relevant data. We performed a metaregression to determine if temporal trends of IE characteristics exist. RESULTS: Fifteen population-based investigations with 2,371 IE cases from seven countries (Denmark, France, Italy, the Netherlands, Sweden, United Kingdom, and United States) from 1969 to 2000 were eligible. Different case definitions and procedures were used to capture all IE cases, including census of existing diagnoses, record-linkage system, and direct contact survey. In the unadjusted regression, there was a decline in the proportion of IE patients with underlying rheumatic heart disease (RHD; 12%; 95% confidence interval [CI], - 21 to - 3%; p = 0.01) and an increase in the proportion of patients undergoing valve surgery (9%; 95% CI, 3 to 16%) per decade. After adjusting for country, the decline in IE cases with underlying RHD became nonsignificant, but the proportions of IE patients undergoing valve surgery increased 7% per decade (95% CI, - 4 to 14%; p = 0.06), and those with underlying prosthetic valve increased 7% per decade (95% CI, - 1 to 16%; p = 0.07). There were no significant temporal trends in the causative organisms. CONCLUSION: Evidence from well-planned, representative IE epidemiologic surveys is scarce in many countries. Available studies suggest a changing distribution of underlying valvular heart disease in patients with IE and an increase in its surgical treatment. [ABSTRACT FROM AUTHOR]

Fusobacterium necrophorum, a rarely encountered but potentially lethal bacterial pathogen, is the cause of Lemierre syndrome, an oropharyngeal infection complicated by jugular vein thrombophlebitis and metastatic septic embolization. We describe an unusual variant of this disease in a man who developed F necrophorum sepsis (associated with extensive inferior vena cava and common femoral vein thrombosis) and multiple abscesses in the lungs after a trauma-associated abscess of the left lower extremity. We highlight the predilection of F necrophorum to cause a potentially fatal septic illness irrespective of its primary focus and emphasize the importance of this bacterium as a cause of considerable morbidity. [ABSTRACT FROM AUTHOR]

Objective: To ascertain the impact of prior antiplatelet and statin therapy on symptomatic embolic events in [corrected] infective endocarditis (IE).Patients and Methods: We studied a retrospective cohort of adult patients with a diagnosis of IE who presented to Mayo Clinic (Rochester, MN) from January 1, 2003, to December 31, 2006. Patients were grouped into those who received treatment before infection or controls who did not receive treatment for both antiplatelet therapy and, separately, statin therapy. Because of the retrospective study design and thus the nonrandomized treatment groups, a propensity score approach was used to account for the confounding factors that may have influenced treatment allocation. Antiplatelet therapy included aspirin, dipyridamole, clopidogrel, ticlopidine or any combination of these agents. Statin therapy included atorvastatin, simvastatin, pravastatin, lovastatin, rosuvastatin, or fluvastatin. The primary end point was a symptomatic embolic event that occurred before or during hospitalization. Multivariable logistic regression was used to assess the propensity-adjusted effects of continuous daily therapy with antiplatelet and statin agents on risk of symptomatic emboli. Likewise, Cox proportional hazards regression was used to test for an independent association with 6-month mortality for each of the treatments.Results: The study cohort comprised 283 patients with [corrected] IE. Twenty-eight patients (24.1%) who received prior continuous antiplatelet therapy developed a symptomatic embolic event compared with 66 (39.5%) who did not receive such treatment. After adjusting for propensity to treat, the effect of antiplatelet therapy on embolic risk was not statistically significant (odds ratio, 0.71; 95% confidence interval [CI], 0.37-1.36; P=.30). Only 14 patients (18.2%) who received prior continuous statin therapy developed a symptomatic embolic event compared with 80 (39.4%) of the 203 patients who did not. After adjusting for propensity to treat with statin therapy, the benefit attributable to statins was significant (odds ratio, 0.30; 95% CI, 0.14-0.62; P=.001). The 6-month mortality rate of the entire cohort was 28% (95% CI, 23%-34%). No significant difference was found in the propensity-adjusted rate of 6-month mortality between patients who had and had not undergone prior antiplatelet therapy (P=.91) or those who had and had not undergone prior statin therapy (P=.87).Conclusion: The rate of symptomatic emboli associated with IE was reduced in patients who received continuous daily statin therapy before onset of IE. Despite fewer embolic events observed in patients who received antiplatelet agents, a significant association was not found after adjusting for propensity factors. A continued evaluation of these drugs and their potential impact on subsequent embolism among IE patients is warranted. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To describe management of patients with permanent pacemaker (PPM)- and implantable cardioverter-defibrillator (ICD)-related endocarditis. PATIENTS AND METHODS: We retrospectively reviewed all cases of infection involving PPMs and ICDs among patients presenting to Mayo Clinic's site in Rochester, MN, between January 1, 1991, and December 31, 2003. Cardiac device-related infective endocarditis (CDIE) was defined as the presence of both vegetation on a device lead or valve and clinical or microbiological evidence of CDIE. Of 189 patients with PPM or ICD infection who were admitted during the study period, 44 met the case definition for CDIE (33 PPM, 11 ICD). RESULTS: The mean +/- SD age of patients was 67 +/- 14 years. Staphylococci (36 [82%]) were the most commonly isolated pathogens. Nearly all patients (43 [98%]) were treated with a combined approach of complete hardware removal and parenteral antibiotics. The median duration of antibiotic treatment after infected device explantation was 28 days (interquartile range, 19-42 days). Device leads were removed percutaneously in 34 cases (77%); only 7 cases (16%) required surgical lead extraction. Percutaneous extraction was uncomplicated in 15 patients with lead vegetation greater than 10 mm in diameter. Six patients (14%) died during hospitalization. Twenty-seven (96%) of 28 patients remained infection free at their last visit (median follow-up, 183 days; intraquartile range, 36-628 days). CONCLUSION: Prompt hardware removal and prolonged parenteral antibiotic administration decrease mortality among patients with CDIE. The presence of a large (> 10 mm in diameter) vegetation on a lead is not a contraindication for percutaneous lead extraction. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To describe the infectious complications of percutaneous vascular closure devices (PVCDs) on the basis of our institutional experience with PVCDs and the published medical literature. PATIENTS AND METHODS: We retrospectively reviewed all cases of PVCD-related Infection seen at the Mayo Clinic in Rochester, Minn, between January 1, 2000, and December 31, 2003, and searched the English language medical literature for all previously published reports. RESULTS: We identified 46 cases in the medical literature and 6 cases from our Institutional database. The median age of patients was 63 years (range, 40-79 years). Diabetes mellitus and obesity were the most common comorbidities. The median Incubation period from device Insertion to presentation with access-site infection was 8 days (range, 2-29 days). The most common presenting symptoms were pain, erythema, fever, swelling, and purulent drainage at the access site. Mycotic pseudoaneurysm (22 cases) was the most common complication. Staphylococcus aureus was responsible for most (75%) of the Infections. All patients underwent surgical debridement, and 54% required reconstructive procedures. The median duration of antibiotic treatment was 28 days (range, 7-42 days). The mortality rate was 6% (3 patients). CONCLUSIONS: Infection associated with PVCD placement is uncommon but is an extremely serious complication. Morbidity is high, and aggressive medical and surgical interventions are required to achieve cure. [ABSTRACT FROM AUTHOR]

Tumour hypoxia promotes poor patient outcomes, with particularly strong evidence for head and neck squamous cell carcinoma (HNSCC). To effectively target hypoxia, therapies require selection biomarkers and preclinical models that can accurately model tumour hypoxia. We established 20 patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) models of HNSCC that we characterised for their fidelity to represent clinical HNSCC in gene expression, hypoxia status and proliferation and that were evaluated for their sensitivity to hypoxia-activated prodrugs (HAPs). PDX models showed greater fidelity in gene expression to clinical HNSCC than cell lines, as did CDX models relative to their paired cell lines. PDX models were significantly more hypoxic than CDX models, as assessed by hypoxia gene signatures and pimonidazole immunohistochemistry, and showed similar hypoxia gene expression to clinical HNSCC tumours. Hypoxia or proliferation status alone could not determine HAP sensitivity across our 20 HNSCC and two non-HNSCC tumour models by either tumour growth inhibition or killing of hypoxia cells in an ex vivo clonogenic assay. In summary, our tumour models provide clinically relevant HNSCC models that are suitable for evaluating hypoxia-targeting therapies; however, additional biomarkers to hypoxia are required to accurately predict drug sensitivity., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The dominant role of non-homologous end-joining in the repair of radiation-induced double-strand breaks identifies DNA-dependent protein kinase (DNA-PK) as an excellent target for the development of radiosensitizers. We report the discovery of a new class of imidazo[4,5- c ]pyridine-2-one DNA-PK inhibitors. Structure-activity studies culminated in the identification of 78 as a nM DNA-PK inhibitor with excellent selectivity for DNA-PK compared to related phosphoinositide 3-kinase (PI3K) and PI3K-like kinase (PIKK) families and the broader kinome, and displayed DNA-PK-dependent radiosensitization of HAP1 cells. Compound 78 demonstrated robust radiosensitization of a broad range of cancer cells in vitro , displayed high oral bioavailability, and sensitized colorectal carcinoma (HCT116/54C) and head and neck squamous cell carcinoma (UT-SCC-74B) tumor xenografts to radiation. Compound 78 also provided substantial tumor growth inhibition of HCT116/54C tumor xenografts in combination with radiation. Compound 78 represents a new, potent, and selective class of DNA-PK inhibitors with significant potential as radiosensitizers for cancer treatment.

Vascular graft infection (VGI) is one of the most serious complications following arterial reconstructive surgery. VGI has received increasing attention over the past decade, but many questions remain regarding its diagnosis and management. In this review, we describe our approach to VGI through multidisciplinary collaboration and discuss decision-making for challenging presentations. This document will concentrate on VGI that impacts both aneurysms and pseudoaneurysms excluding the ascending thoracic aorta., Competing Interests: Potential conflicts of interest . L. M. B. reports royalty payments (authorship duties) from UpToDate, Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Vascular graft infection (VGI) is one of the most serious complications following arterial reconstructive surgery. VGI has received increasing attention over the past decade, but many questions remain regarding its diagnosis and management. In this review, we describe our approach to VGI through multidisciplinary collaboration and discuss decision making for challenging presentations. This review will concentrate on VGI that impacts both aneurysms and pseudoaneurysms excluding the ascending thoracic aorta., Competing Interests: Potential conflicts of interest. L. M. B. reports royalty payments (authorship duties) from UpToDate, Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Given the challenges of conventional therapies in managing right-sided infective endocarditis (RSIE), percutaneous mechanical aspiration (PMA) of vegetations has emerged as a novel treatment option. Data on trends, characteristics, and outcomes of PMA, however, have largely been limited to case reports and case series., Aims: The aim of the current investigation was to provide a descriptive analysis of PMA in the United States and to profile the frequency of PMA with a temporal analysis and the patient cohort., Methods: The International Classification of Diseases, 10th Revision codes were used to identify patients with RSIE in the national (nationwide) inpatient sample (NIS) database between 2016 and 2020. The clinical characteristics and temporal trends of RSIE hospitalizations in patients who underwent PMA was profiled., Results: An estimated 117,955 RSIE-related hospital admissions in the United States over the 5-year study period were estimated and 1675 of them included PMA. Remarkably, the rate of PMA for RSIE increased 4.7-fold from 2016 (0.56%) to 2020 (2.62%). Patients identified with RSIE who had undergone PMA were young (medial age 36.5 years) and had few comorbid conditions (median Charlson Comorbidity Index, 0.6). Of note, 36.1% of patients had a history of hepatitis C infection, while only 9.9% of patients had a cardiovascular implantable electronic device. Staphylococcus aureus was the predominant (61.8%) pathogen. Concomitant transvenous lead extraction and cardiac valve surgery during the PMA hospitalization were performed in 18.2% and 8.4% of admissions, respectively. The median hospital stay was 19.0 days, with 6.0% in-hospital mortality., Conclusions: The marked increase in the number of PMA procedures in the United States suggests that this novel treatment option has been embraced as a useful tool in select cases of RSIE. More work is needed to better define indications for the procedure and its efficacy and safety., (© 2024 Wiley Periodicals LLC.)

Transplantable in vivo CRISPR/Cas9 knockout screens, in which cells are edited in vitro and inoculated into mice to form tumours, allow evaluation of gene function in a cancer model that incorporates the multicellular interactions of the tumour microenvironment. To improve our understanding of the key parameters for success with this method, we investigated the choice of cell line, mouse host, tumour harvesting timepoint and guide RNA (gRNA) library size. We found that high gRNA (80-95%) representation was maintained in a HCT116 subline transduced with the GeCKOv2 whole-genome gRNA library and transplanted into NSG mice when tumours were harvested at early (14 d) but not late time points (38-43 d). The decreased representation in older tumours was accompanied by large increases in variance in gRNA read counts, with notable expansion of a small number of random clones in each sample. The variable clonal dynamics resulted in a high level of 'noise' that limited the detection of gRNA-based selection. Using simulated datasets derived from our experimental data, we show that considerable reductions in count variance would be achieved with smaller library sizes. Based on our findings, we suggest a pathway to rationally design adequately powered in vivo CRISPR screens for successful evaluation of gene function., (© 2023. The Author(s).)

Poly(ADP-ribose)polymerase inhibitors (PARPi) are used for treatment of tumours with a defect in homologous recombination (HR) repair. Combination with radio- or chemotherapy could broaden their applicability but a major hurdle is enhancement of normal tissue toxicity. Development of hypoxia-activated prodrugs (HAPs) of PARPi has potential to restrict PARP inhibition to tumours thereby avoiding off-target toxicity. We have designed and synthesised phenolic derivatives of olaparib (termed phenolaparibs) and corresponding ether-linked HAPs. Phenolaparib cytotoxicity in HR-proficient and deficient cell lines was consistent with inhibition of PARP-1. Prodrugs were deactivated relative to phenolaparibs in biochemical PARP-1 inhibition assays, and cell culture. Prodrug 7 was selectively converted to phenolaparib 4 under hypoxia and demonstrated hypoxia-selective cytotoxicity, including chemosensitisation of HR-proficient cells in combination with temozolomide. This work demonstrates the feasibility of a HAP approach to PARPi for use in combination therapies., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)