Prediction of carcinogenic potential of chemicals using repeated-dose (13-week) toxicity data

AbstractSub-chronic toxicity studies of 163 non-genotoxic chemicals were evaluated in order to predict the tumour outcome of 24-month rat carcinogenicity studies obtained from the EFSA and ToxRef databases. Hundred eleven of the 148 chemicals that did not induce putative preneoplastic lesions in the sub-chronic study also did not induce tumours in the carcinogenicity study (True Negatives). Cellular hypertrophy appeared to be an unreliable predictor of carcinogenicity. The negative predictivity, the measure of the compounds evaluated that did not show any putative preneoplastic lesion in de sub-chronic studies and were negative in the carcinogenicity studies, was 75%, whereas the sensitivity, a measure of the sub-chronic study to predict a positive carcinogenicity outcome was only 5%. The specificity, the accuracy of the sub-chronic study to correctly identify non-carcinogens was 90%. When the chemicals which induced tumours generally considered not relevant for humans (33 out of 37 False Negatives) are classified as True Negatives, the negative predictivity amounts to 97%. Overall, the results of this retrospective study support the concept that chemicals showing no histopathological risk factors for neoplasia in a sub-chronic study in rats may be considered non-carcinogenic and do not require further testing in a carcinogenicity study

Cerebrovascular Autoregulation in Preterm Infants During and After Surgical Ligation of the Ductus Arteriosus, a Comparison Between Two Surgical Approaches

Objective: During ligation of the ductus arteriosus, cerebrovascular autoregulation (CAR) may deteriorate. It is unknown whether different surgical approaches affect changes in CAR differently. The objective of this study was to compare the potential change in CAR in preterm infants during and after ligation comparing two surgical approaches: sternotomy and posterolateral thoracotomy. Design: This was an observational cohort pilot study. Setting: Level III NICU. Patients: Preterm infants (GA < 32 weeks) requiring ductal ligation were eligible for inclusion. Interventions: Halfway the study period, our standard surgical approach changed from a posterolateral thoracotomy to sternotomy. We analyzed dynamic CAR, using an index of autoregulation (COx) correlating cerebral tissue oxygen saturation and invasive arterial blood pressure measurements, before, during, and after ligation, in relation to the two approaches. Measurements and Main Results: Of nine infants, four were approached by thoracotomy and five by sternotomy. Median GA was 26 (range: 24.9–27.9) weeks, median birth weight (BW) was 800 (640–960) grams, and median post-natal age (PNA) was 18 (15–30) days, without differences between groups. COx worsened significantly more during and after thoracotomy from baseline (Δρ from baseline: during surgery: Δ + 0.32, at 4 h: Δ + 0.36, at 8 h: Δ + 0.32, at 12 h: Δ + 0.31) as compared with sternotomy patients (Δρ from baseline: during surgery: Δ + 0.20, at 4 h: Δ + 0.05, at 8 h: Δ + 0.15, at 12 h: Δ + 0.11) (F = 6.50; p = 0.038). Conclusions: In preterm infants, CAR reduced significantly during and up to 12 h after ductal ligation in all infants, but more evident during and after posterolateral thoracotomy as compared with sternotomy. These results need to be confirmed in a larger population

Current status and opportunities for therapeutic drug monitoring in the treatment of tuberculosis

Contains fulltext : 172247.pdf (Publisher’s version ) (Open Access

What are Effective Strategies to Reduce Low-Value Care? An Analysis of 121 Randomized Deimplementation Studies

Background: Low-value care is healthcare leading to no or little clinical benefit for the patient. The best (combinations of) interventions to reduce low-value care are unclear. Purpose: To provide an overview of randomized controlled trials (RCTs) evaluating deimplementation strategies, to quantify the effectiveness and describe different combinations of strategies. Methods: Analysis of 121 RCTs (1990-2019) evaluating a strategy to reduce low-value care, identified by a systematic review. Deimplementation strategies were described and associations between strategy characteristics and effectiveness explored. Results: Of 109 trials comparing deimplementation to usual care, 75 (69%) reported a significant reduction of low-value healthcare practices. Seventy-three trials included in a quantitative analysis showed a median relative reduction of 17% (IQR 7%-42%). The effectiveness of deimplementation strategies was not associated with the number and types of interventions applied. Conclusions and Implications: Most deimplementation strategies achieved a considerable reduction of low-value care. We found no signs that a particular type or number of interventions works best for deimplementation. Future deimplementation studies should map relevant contextual factors, such as the workplace culture or economic factors. Interventions should be tailored to these factors and provide details regarding sustainability of the effect.</p

Approaches and considerations for the assessment of immunotoxicity for environmental chemicals: A workshop summary

AbstractAs experience is gained with toxicology testing and as new assays and technologies are developed, it is critical for stakeholders to discuss opportunities to advance our overall testing strategies. To facilitate these discussions, a workshop on practices for assessing immunotoxicity for environmental chemicals was held with the goal of sharing perspectives on immunotoxicity testing strategies and experiences, developmental immunotoxicity (DIT), and integrated and alternative approaches to immunotoxicity testing. Experiences across the chemical and pharmaceutical industries suggested that standard toxicity studies, combined with triggered-based testing approaches, represent an effective and efficient approach to evaluate immunotoxic potential. Additionally, discussions on study design, critical windows, and new guideline approaches and experiences identified important factors to consider before initiating DIT evaluations including assay choice and timing and the impact of existing adult data. Participants agreed that integrating endpoints into standard repeat-dose studies should be considered for fulfilling any immunotoxicity testing requirements, while also maximizing information and reducing animal use. Participants also acknowledged that in vitro evaluation of immunosuppression is complex and may require the use of multiple assays that are still being developed. These workshop discussions should contribute to developing an effective but more resource and animal efficient approach for evaluating chemical immunotoxicity

What are Effective Strategies to Reduce Low-Value Care?: An Analysis of 121 Randomized Deimplementation Studies

BACKGROUND: Low-value care is healthcare leading to no or little clinical benefit for the patient. The best (combinations of) interventions to reduce low-value care are unclear. PURPOSE: To provide an overview of randomized controlled trials (RCTs) evaluating deimplementation strategies, to quantify the effectiveness and describe different combinations of strategies. METHODS: Analysis of 121 RCTs (1990-2019) evaluating a strategy to reduce low-value care, identified by a systematic review. Deimplementation strategies were described and associations between strategy characteristics and effectiveness explored. RESULTS: Of 109 trials comparing deimplementation to usual care, 75 (69%) reported a significant reduction of low-value healthcare practices. Seventy-three trials included in a quantitative analysis showed a median relative reduction of 17% (IQR 7%-42%). The effectiveness of deimplementation strategies was not associated with the number and types of interventions applied. CONCLUSIONS AND IMPLICATIONS: Most deimplementation strategies achieved a considerable reduction of low-value care. We found no signs that a particular type or number of interventions works best for deimplementation. Future deimplementation studies should map relevant contextual factors, such as the workplace culture or economic factors. Interventions should be tailored to these factors and provide details regarding sustainability of the effect

Protocol for a prospective, longitudinal cohort study on the effect of arterial disease level on the outcomes of supervised exercise in intermittent claudication: the ELECT Registry

Introduction Despite guideline recommendations advocating conservative management before invasive treatment in intermittent claudication, early revascularisation remains widespread in patients with favourable anatomy. The aim of the Effect of Disease Level on Outcomes of Supervised Exercise in Intermittent Claudication Registry is to determine the effect of the location of stenosis on the outcomes of supervised exercise in patients with intermittent claudication due to peripheral arterial disease. Methods and analysis This multicentre prospective cohort study aims to enrol 320 patients in 10 vascular centres across the Netherlands. All patients diagnosed with intermittent claudication (peripheral arterial disease: Fontaine II/Rutherford 1–3), who are considered candidates for supervised exercise therapy by their own physicians are appropriate to participate. Participants will receive standard care, meaning supervised exercise therapy first, with endovascular or open revascularisation in case of insufficient effect (at the discretion of patient a

Targeting and translocation of the two lipoproteins in Escherichia coli via the SRP/Sec/YidC pathway.

In Escherichia coli, two main protein targeting pathways to the inner membrane exist: the SecB pathway for the essentially posttranslational targeting of secretory proteins and the SRP pathway for cotranslational targeting of inner membrane proteins (IMPs). At the inner membrane both pathways converge at the Sec translocase, which is capable of both linear transport into the periplasm and lateral transport into the lipid bilayer. The Sec-associated YidC appears to assist the lateral transport of IMPs from the Sec translocase into the lipid bilayer. It should be noted that targeting and translocation of only a handful of secretory proteins and IMPs have been studied. These model proteins do not include lipoproteins. Here, we have studied the targeting and translocation of two secretory lipoproteins, the murein lipoprotein and the bacteriocin release protein, using a combined in vivo and in vitro approach. The data indicate that both murein lipoprotein and bacteriocin release protein require the SRP pathway for efficient targeting to the Sec translocase. Furthermore, we show that YidC plays an important role in the targeting/translocation of both lipoproteins