Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny - Part IV: the ECETOC and CLE Proposal for a Thyroid Function-Related Neurodevelopmental Toxicity Testing and Assessment Scheme (Thyroid-NDT-TAS).

Following the European Commission Endocrine Disruptor Criteria, substances shall be considered as having endocrine disrupting properties if they (a) elicit adverse effects, (b) have endocrine activity, and (c) the two are linked by an endocrine mode-of-action (MoA) unless the MoA is not relevant for humans. A comprehensive, structured approach to assess whether substances meet the Endocrine Disruptor Criteria for the thyroid modality (EDC-T) is currently unavailable. Here, the European Centre for Ecotoxicology and Toxicology of Chemicals Thyroxine Task Force and CropLife Europe propose a Thyroid Function-Related Neurodevelopmental Toxicity Testing and Assessment Scheme (Thyroid-NDT-TAS). In Tier 0, before entering the Thyroid-NDT-TAS, all available in vivo, in vitro and in silico data are submitted to weight-of-evidence (WoE) evaluations to determine whether the substance of interest poses a concern for thyroid disruption. If so, Tier 1 of the Thyroid-NDT-TAS includes an initial MoA and human relevance assessment (structured by the key events of possibly relevant adverse outcome pathways) and the generation of supportive in vitro/in silico data, if relevant. Only if Tier 1 is inconclusive, Tier 2 involves higher-tier testing to generate further thyroid- and/or neurodevelopment-related data. Tier 3 includes the final MoA and human relevance assessment and an overarching WoE evaluation to draw a conclusion on whether, or not, the substance meets the EDC-T. The Thyroid-NDT-TAS is based on the state-of-the-science, and it has been developed to minimise animal testing. To make human safety assessments more accurate, it is recommended to apply the Thyroid-NDT-TAS during future regulatory assessments.

Formal Insertion of Alkenes Into C(sp3 )-F Bonds Mediated by Fluorine-Hydrogen Bonding.

C-F Insertion reactions represent an attractive approach to prepare valuable fluorinated compounds. The high strength of C-F bonds and the low reactivity of the fluoride released upon C-F bond cleavage, however, mean that examples of such processes are extremely scarce in the literature. Here we report a reaction system that overcomes these challenges using hydrogen bond donors that both activate C-F bonds and allow for downstream reactions with fluoride. In the presence of hexafluoroisopropanol, benzyl and propargyl fluorides undergo efficient formal C-F bond insertion across α-fluorinated styrenes. This process, which does not require any additional fluorinating reagent, occurs under mild conditions and delivers products featuring the gem-difluoro motif, which is attracting increasing interest in medicinal chemistry. Moreover, readily available organic bromides can be engaged directly in a one-pot process that avoids the isolation of organic fluorides.

Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny-part III: how is substance-mediated thyroid hormone imbalance in pregnant/lactating rats or their progeny related to neurodevelopmental effects?

This review investigated which patterns of thyroid- and brain-related effects are seen in rats upon gestational/lactational exposure to 14 substances causing thyroid hormone imbalance by four different modes-of-action (inhibition of thyroid peroxidase, sodium-iodide symporter and deiodinase activities, enhancement of thyroid hormone clearance) or to dietary iodine deficiency. Brain-related parameters included motor activity, cognitive function, acoustic startle response, hearing function, periventricular heterotopia, electrophysiology and brain gene expression. Specific modes-of-action were not related to specific patterns of brain-related effects. Based upon the rat data reviewed, maternal serum thyroid hormone levels do not show a causal relationship with statistically significant neurodevelopmental effects. Offspring serum thyroxine together with offspring serum triiodothyronine and thyroid stimulating hormone appear relevant to predict the likelihood for neurodevelopmental effects. Based upon the collated database, thresholds of ≥60%/≥50% offspring serum thyroxine reduction and ≥20% and statistically significant offspring serum triiodothyronine reduction indicate an increased likelihood for statistically significant neurodevelopmental effects; accuracies: 83% and 67% when excluding electrophysiology (and gene expression). Measurements of brain thyroid hormone levels are likely relevant, too. The extent of substance-mediated thyroid hormone imbalance appears more important than substance mode-of-action to predict neurodevelopmental impairment in rats. Pertinent research needs were identified, e.g. to determine whether the phenomenological offspring thyroid hormone thresholds are relevant for regulatory toxicity testing. The insight from this review shall be used to suggest a tiered testing strategy to determine whether gestational/lactational substance exposure may elicit thyroid hormone imbalance and potentially also neurodevelopmental effects.

Application of a new approach method (NAM) for inhalation risk assessment.

The US Environmental Protection Agency (USEPA) and other regulatory authorities have been working to utilize in vitro studies with human cells and in silico modelling to reduce the use of vertebrate animals for evaluating chemical risk. Using the Source-to-Outcome framework, a novel mathematical procedure was developed to estimate the human equivalent concentration (HEC) for inhalation risk assessment based upon the relevant aerosol characterization, respiratory dosimetry modelling, and endpoints derived from an in vitro assay using human respiratory epithelial tissue. The procedure used the retained doses at the various areas of the inhalation tract estimated from a computational fluid-particle dynamics (CFPD) model coupled with a simple clearance model. The effect of exposure was derived from an in vitro assay. The magnitude of exposure and the particle size distributions (PSDs) of the external aerosol droplets were obtained from Unit Exposure values published by the USEPA and published monitoring studies, respectively. The Source-to-Outcome approach incorporates external and internal exposure metrics with the toxicity pathway. The information was then integrated to conduct a risk assessment for agricultural operators exposed to products containing chlorothalonil (CTN), a broad-spectrum fungicide. The HECs for three different PSDs considered in this work ranged from 0.043 to 0.112 mg-CTN/L for nasal and oral breathing. These were compared with the estimated average daily exposure concentration for six representative application scenarios. The resulting margins of exposure (MOEs) ranged from 230 to 70,000 depending on the application scenario. This New Assessment Method (NAM) that combined human in silico and human in vitro methods, eliminated the typical uncertainties associated with extrapolation from rodent studies, with their associated interspecies toxicokinetics and toxicodynamics differences. The intraspecies toxicodynamics and toxicokinetics, are still relevant and may need to be used in an inhalation risk assessment. The NAM presented in this work is not chemical-specific and may be applied to conduct an inhalation risk assessment for workers as well as bystanders who could be exposed to aerosol particles of any cytotoxic respiratory irritant.

Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny - part II: how can key events of relevant adverse outcome pathways be addressed in toxicological assessments?

The current understanding of thyroid-related adverse outcome pathways (AOPs) with adverse neurodevelopmental outcomes in mammals has been reviewed. This served to establish if standard rodent toxicity test methods and in vitro assays allow identifying thyroid-related modes-of-action potentially leading to adverse neurodevelopmental outcomes, and the human relevance of effects - in line with the European Commission's Endocrine Disruptor Criteria. The underlying hypothesis is that an understanding of the key events of relevant AOPs provides insight into differences in incidence, magnitude, or species sensitivity of adverse outcomes. The rodent studies include measurements of serum thyroid hormones, thyroid gland pathology and neurodevelopmental assessments, but do not directly inform on specific modes-of-action. Opportunities to address additional non-routine parameters reflecting critical events of AOPs in toxicological assessments are presented. These parameters appear relevant to support the identification of specific thyroid-related modes-of-action, provided that prevailing technical limitations are overcome. Current understanding of quantitative key event relationships is often weak, but would be needed to determine if the triggering of a molecular initiating event will ultimately result in an adverse outcome. Also, significant species differences in all processes related to thyroid hormone signalling are evident, but the biological implications thereof (including human relevance) are often unknown. In conclusion, careful consideration of the measurement (e.g. timing, method) and interpretation of additional non-routine parameters is warranted. These findings will be used in a subsequent paper to propose a testing strategy to identify if a substance may elicit maternal thyroid hormone imbalance and potentially also neurodevelopmental effects in the progeny.

Temperature and immigration effects on quorum sensing in the biofilms of anaerobic membrane bioreactors.

Quorum sensing (QS), a microbial communication mechanism modulated by acyl homoserine lactone (AHL) molecules impacts biofilm formation in bioreactors. This study investigated the effects of temperature and immigration on AHL levels and biofouling in anaerobic membrane bioreactors. The hypothesis was that the immigrant microbial community would increase the AHL-mediated QS, thus stimulating biofouling and that low temperatures would exacerbate this. We observed that presence of immigrants, especially when exposed to low temperatures indeed increased AHL concentrations and fouling in the biofilms on the membranes. At low temperature, the concentrations of the main AHLs observed, N-dodecanoyl-L-homoserine lactone and N-decanoyl-L-homoserine lactone, were significantly higher in the biofilms than in the sludge and correlated significantly with the abundance of immigrant bacteria. Apparently low temperature, immigration and denser community structure in the biofilm stressed the communities, triggering AHL production and excretion. These insights into the social behaviour of reactor communities responding to low temperature and influx of immigrants have implications for biofouling control in bioreactors.

Toward a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny - part I: which parameters from human studies are most relevant for toxicological assessments?

The 2018 European Food Safety Authority/European Chemicals Agency Guidance on the Identification of Endocrine Disruptors lacks clarity on how the presence or absence of substance-induced maternal thyroid hormone imbalance, or the potential for subsequent deleterious consequences in child neurodevelopment, should be established by toxicological assessments. To address these uncertainties, this narrative review evaluates human evidence on how altered maternal thyroid function may be associated with child neurodevelopmental outcomes; and seeks to identify parameters in human studies that appear most relevant for toxicological assessments. Serum levels of free thyroxine (fT4) and thyroid stimulating hormone (TSH) are most frequently measured when assessing thyroid function in pregnant women, whereas a broad spectrum of neurodevelopmental parameters is used to evaluate child neurodevelopment. The human data confirms an association between altered maternal serum fT4 and/or TSH and increased risk for child neurodevelopmental impairment. Quantitative boundaries of effects indicative of increased risks need to be established. Moreover, it is unknown if altered serum levels of total T4, free or total triiodothyronine, or parameters unrelated to serum thyroid hormones might be more relevant indicators of such effects. None of the human studies established a link between substance-mediated liver enzyme induction and increased serum thyroid hormone clearance, let alone further to child neurodevelopmental impairment. This review identifies research needs to contribute to the development of toxicity testing strategies, to reliably predict whether substances have the potential to impair child neurodevelopment via maternal thyroid hormone imbalance.

Renal injury and hepatic effects from the methylimidazolium ionic liquid M8OI in mouse.

The ionic liquid 1-octyl-3-methylimidazolium (M8OI) has been found in the environment and identified as a hazard for triggering the liver disease primary biliary cholangitis (PBC). Given limited toxicity data for M8OI and other structurally-related ionic liquids, target organs for M8OI toxicity were examined. Adult male C57Bl6 mice were acutely exposed to 0-10 mg/kg body weight M8OI via 2 intraperitoneal injections (time zero and 18 h) and effects examined at 24 h. At termination, tissue histopathology, serum and urinary endpoints were examined. No overt pathological changes were observed in the heart and brain. In contrast, focal and mild to multifocal and moderate degeneration with a general trend for an increase in severity with increased dose was observed in the kidney. These changes were accompanied by a dose-dependent increased expression of Kim1 in kidney tissue, marked elevations in urinary Kim1 protein and a dose-dependent increase in serum creatinine. Hepatic changes were limited to a significant dose-dependent loss of hepatic glycogen and a mild but significant increase in portal tract inflammatory recruitment and/or fibroblastic proliferation accompanied by a focal fibrotic change. Cultured mouse tissue slices reflected these in vivo effects in that dose-dependent injury was observed in kidney slices but not in the liver. Kidney slices accumulated higher levels of M8OI than liver slices (e.g. at 10 µM, greater than 4 fold) and liver slices where markedly more active in the metabolism of M8OI. These data indicate that the kidney is a target organ for the toxic effects of M8OI accompanied by mild cholangiopathic changes in the liver after intraperitoneal administration.

Long-term Impact of Sewage Sludge Application on biovar : An Evaluation Using Meta-Analysis.

The Long-Term Sludge Experiment (LTSE) began in 1994 at nine UK field sites as part of continuing research into the effects of sludge-borne heavy metals on soil fertility. The long-term effects of Zn, Cu, and Cd on the most probable numbers of cells (MPN) of biovar were monitored for 8 yr in sludge-amended soils. To assess the statutory limits set by the UK Sludge (Use in Agriculture) Regulations, the experimental data were reviewed using statistical methods of meta-analysis. Previous LTSE studies have focused predominantly on statistical significance rather than effect size, whereas meta-analysis focuses on the magnitude and direction of an effect, i.e., the practical significance rather than its statistical significance. Results showed Zn to be the most toxic element causing an overall significant decrease in MPN of -26.6% during the LTSE. The effect of Cu showed no significant effect on MPN at concentrations below the UK limits, although a -5% decrease in MPN was observed in soils where total Cu ranged from 100 to <135 mg kg. Overall, there was nothing to indicate that Cd had a significant effect on MPN below the current UK statutory limit. In summary, the UK statutory limit for Zn appears to be insufficient for protecting from Zn toxicity effects.

Undifferentiated HepaRG cells show reduced sensitivity to the toxic effects of M8OI through a combination of CYP3A7-mediated oxidation and a reduced reliance on mitochondrial function.

The methylimidazolium ionic liquid M8OI (1-octyl-3-methylimidazolium chloride, also known as [C8mim]Cl) has been detected in the environment and may represent a hazard trigger for the autoimmune liver disease primary biliary cholangitis, based in part on studies using a rat liver progenitor cell. The effect of M8OI on an equivalent human liver progenitor (undifferentiated HepaRG cells; u-HepaRG) was therefore examined. u-HepaRG cells were less sensitive (>20-fold) to the toxic effects of M8OI. The relative insensitivity of u-HepaRG cells to M8OI was in part, associated with a detoxification by monooxygenation via CYP3A7 followed by further oxidation to a carboxylic acid. Expression of CYP3A7 - in contrast to the related adult hepatic CYP3A4 and CYP3A5 forms - was confirmed in u-HepaRG cells. However, blocking M8OI metabolism with ketoconazole only partly sensitized u-HepaRG cells. Despite similar proliferation rates, u-HepaRG cells consumed around 75% less oxygen than B-13 cells, reflective of reduced dependence on mitochondrial activity (Crabtree effect). Replacing glucose with galactose, resulted in an increase in u-HepaRG cell sensitivity to M8OI, near similar to that seen in B-13 cells. u-HepaRG cells therefore show reduced sensitivity to the toxic effects of M8OI through a combination of metabolic detoxification and their reduced reliance on mitochondrial function.

Intravenous versus oral acetaminophen for pain and quality of recovery after ambulatory spine surgery: a randomized controlled trial.

INTRODUCTION: As ambulatory spine surgery increases, efficient recovery and discharge become essential. Multimodal analgesia is superior to opioids alone. Acetaminophen is a central component of multimodal protocols and both intravenous and oral forms are used. While some advantages for intravenous acetaminophen have been touted, prospective studies with patient-centered outcomes are lacking in ambulatory spine surgery. A substantial cost difference exists. We hypothesized that intravenous acetaminophen would be associated with fewer opioids and better recovery. METHODS: Patients undergoing ambulatory spine surgery were randomized to preoperative oral placebo and intraoperative intravenous acetaminophen or preoperative oral acetaminophen. All patients received general anesthesia and multimodal analgesia. The primary outcome was 24-hour opioid use in intravenous morphine milligram equivalents (MMEs), beginning with arrival to the postanesthesia care unit (PACU). Secondary outcomes included pain, Quality of Recovery (QoR)-15 scores, postoperative nausea and vomiting, recovery time, and correlations between pain catastrophizing, QoR-15, and pain. RESULTS: A total of 82 patients were included in final analyses. Demographics were similar between groups. For the primary outcome, the median 24-hour MMEs did not differ between groups (12.6 (4.0, 27.1) vs 12.0 (4.0, 29.5) mg, p=0.893). Postoperative pain ratings, PACU MMEs, QoR-15 scores, and recovery time showed no differences. Spearman's correlation showed a moderate negative correlation between postoperative opioid use and QoR-15. CONCLUSION: Intravenous acetaminophen was not superior to the oral form in ambulatory spine surgery patients. This does not support routine use of the more expensive intravenous form to improve recovery and accelerate discharge. TRIAL REGISTRATION NUMBER: NCT04574778.

The methylimidazolium ionic liquid M8OI is a substrate for OCT1 and p-glycoprotein-1 in rat.

The methylimidazolium ionic liquid M8OI was recently found to be present in both the environment and man. In this study, M8OI disposition and toxicity were examined in an established rat progenitor-hepatocyte model. The progenitor B-13 cell was approx. 13 fold more sensitive to the toxic effects of M8OI than the hepatocyte B-13/H cell. However, this difference in sensitivity was not associated with a difference in metabolic capacities. M8OI toxicity was significantly decreased in a dose-dependent manner by co-addition of the OCT1 (SLC22A1) inhibitor clonidine, but not by OCT2 or OCT3 inhibitors in B-13 cells. M8OI toxicity was also dose-dependently increased by the co-addition of p-glycoprotein-1 (ABCB1B, multi drug resistant protein 1 (MDR1)) substrates/inhibitors. Excretion of B-13-loaded fluorophore Hoechst 33342 was also inhibited by the p-glycoproteins substrate cyclosporin A and by M8OI in a dose-dependent manner. Comparing levels of OCT and p-glycoprotein transcripts and proteins in B-13 and B-13/H cells suggest that the lower sensitivity to M8OI in B-13/H cells is predominantly associated with their higher expression of p-glycoprotein-1. These data together therefore suggest that a determinant in M8OI toxicity in rats is the expression and activity of the p-glycoprotein-1 transporter.

Early Diet Liberalization After Anterior Lumbar Interbody Fusion Improves Postoperative Recovery.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVES: The objective of this study was to assess the impact of diet liberalization on short-term outcomes in patients undergoing anterior interbody lumbar fusion (ALIF). METHODS: A retrospective review was performed for patients undergoing ALIF at our tertiary care center institution from 2010 to 2022. Electronic medical records were reviewed for demographics, surgical characteristics, and 90-day postoperative outcomes. RESULTS: We included 515 patients in this study with 102 patients receiving a full diet on the same day as their operation. All other patients had a delay of at least 1 day (average 1.6 days) until a full diet was provided. This group was found to have a higher rate of postoperative ileus (10.2% vs 2.9%) and urinary retention (16.0% vs 3.9%). The readmission rate and percent of patients presenting to the emergency department within 90 days postoperatively were similar. On multivariate regression analysis, same-day, full-diet patients had decreased odds of developing urinary retention (OR = .17) and a shorter length of hospital stay (Estimate: -.99). Immediate full diet had no impact on the development of ileus (OR: .33). CONCLUSIONS: An immediate postoperative full diet following an anterior approach to the lumbar spine was not found to be associated with an increased risk of postoperative ileus in patients deemed appropriate for early diet liberalization. Moreover, an early full diet was found to reduce length of hospitalization and risk of postoperative urinary retention. Reconsideration of postoperative diet protocols may help optimize patient outcomes and recovery.

Comparison of clinical estimations and radiological measurements in the context of paediatric cervical masses: How accurate are we?

OBJECTIVES: Cervical masses represent a common presentation to the paediatric ENT outpatient clinic. Despite their high prevalence, few represent an underlying malignant pathology. Currently, there is no universally accepted algorithm for management of such cases in the United Kingdom. Local guidance often centres around clinical interpretation of size when determining the need for investigation. With such emphasis placed on size, the authors sought to investigate the accuracy of physician palpation and in turn explore the validity of common referral pathways. METHODS: A retrospective methodology was used to address the research objective. All paediatric ultrasound scans conducted during a 24-month period were reviewed to compare the clinical and radiological assessments of diameter. A 2 tailed paired student's t-test was selected to evaluate the differences between the two measurements and ultimately assess clinician accuracy. RESULTS: 753 paediatric cervical ultrasound scans were conducted during the 2-year period. Initial analysis identified three discrete ultrasonographically diagnostic groups: lymph nodes (n = 532), non-lymph node masses (n = 162) and normal anatomy (n = 59). Further analysis of clinical estimation and radiological measurement demonstrated a statistically significant difference (p < 0.02) for the lymph-node group. A statistically significant difference was not demonstrated within the non-lymph node group (p = 0.66). When clinician assessment resulted in a value outside of what was considered accurate, lymph node sizes were predominantly overestimated (62/91, 68%). Conversely, non-lymph node masses where the clinical measurement was not within 5 mm of the ultrasound measurement were more commonly underestimated in size (11/45, 55%) but this was not statistically significant. CONCLUSIONS: Our study demonstrates a statistically significant tendency for clinicians to overestimate paediatric cervical lymphadenopathy. Calliper measurement may further improve accuracy of assessment.

Mitigation of membrane biofouling in membrane bioreactor treating sewage by novel quorum quenching strain of Acinetobacter originating from a full-scale membrane bioreactor.

A novel quorum quenching (QQ) strain, Acinetobacter guillouiae ST01, was isolated from a full-scale membrane bioreactor (MBR) and characterized for its QQ activities. Batch reactor studies at lab-scale showed that A. guillouiae ST01 exhibited higher QQ activity against acyl homoserine lactones (AHLs) with an oxo group compared to those without an oxo group. The organism was then inoculated (10%) in an MBR (Q-MBR) treating sewage over 48 days and was found to reduce quorum sensing (QS) activity by reducing AHL concentrations in the sludge and the biofilm of the Q-MBR. The concentration of polysaccharides was reduced up to 30% in both the biofilm and sludge relative to the control, whereas protein concentrations were reduced by 40% and 47% in the sludge and biofilm, respectively. The Q-MBR fouling rates were halved. These results indicate that A. guillouiae ST01 is a promising strain for biofouling reduction in MBR treating real wastewater.

The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver.

A methylimidizolium ionic liquid (M8OI) was recently found to be contaminating the environment and to be related to and/or potentially a component of an environmental trigger for the autoimmune liver disease primary biliary cholangitis (PBC). The aims of this study were to investigate human exposure to M8OI, hepatic metabolism and excretion. PBC patient and control sera were screened for the presence of M8OI. Human livers were perfused with 50µM M8OI in a closed circuit and its hepatic disposition examined. Metabolism was examined in cultured human hepatocytes and differentiated HepaRG cells by the addition of M8OI and metabolites in the range 10-100 µM. M8OI was detected in the sera from 5/20 PBC patients and 1/10 controls. In perfused livers, M8OI was cleared from the plasma with its appearance - primarily in the form of its hydroxylated (HO8IM) and carboxylated (COOH7IM) products - in the bile. Metabolism was reflected in cultured hepatocytes with HO8IM production inhibited by the cytochrome P450 inhibitor ketoconazole. Further oxidation of HO8IM to COOH7IM was sequentially inhibited by the alcohol and acetaldehyde dehydrogenase inhibitors 4-methyl pyrazole and disulfiram respectively. Hepatocytes from 1 donor failed to metabolise M8OI to COOH7IM over a 24 h period. These results demonstrate exposure to M8OI in the human population, monooxygenation by cytochromes P450 followed by alcohol and acetaldehyde dehydrogenase oxidation to a carboxylic acid that are excreted, in part, via the bile in human liver.

Diversity of Acyl Homoserine Lactone Molecules in Anaerobic Membrane Bioreactors Treating Sewage at Psychrophilic Temperatures.

This study explores the types of acyl homoserine lactone (AHL) and their concentrations in different compartments of different conventional anaerobic bioreactors: (i) an upflow anaerobic membrane bioreactor (UAnMBR, biofilm/mixed liquor (sludge)); (ii) an anaerobic membrane bioreactor (AnMBR, biofilm/mixed liquor (sludge)); and (iii) an upflow sludge blanket (UASB, sludge only), all operating at 15 °C. Ten types of the AHL, namely C4-HSL, 3-oxo-C4-HSL, C6-HSL, 3-oxo-C6-HSL, C8-HSL, 3-oxo-C8-HSL, C10-HSL, 3-oxo-C10-HSL, C12-HSL, and 3-oxo-C12-HSL, which were investigated in this study, were found in UAnMBR and UASB, whilst only six of them (C4-HSL, 3-oxo-C4-HSL, C8-HSL, C10-HSL, 3-oxo-C10-HSL, and C12-HSL) were found in AnMBR. Concentrations of total AHL were generally higher in the biofilm than the sludge for both membrane bioreactors trialed. C10-HSL was the predominant AHL found in all reactors (biofilm and sludge) followed by C4-HSL and C8-HSL. Overall, the UAnMBR biofilm and sludge had 10-fold higher concentrations of AHL compared to the AnMBR. C10-HSL was only correlated with bacteria (p < 0.05), whilst other types of AHL were correlated with both bacteria and archaea. This study improves our understanding of AHL-mediated Quorum Sensing (QS) in the biofilms/sludge of UAnMBR and AnMBR, and provides new information that could contribute to the development of quorum quenching anti-fouling strategies in such systems.

Postoperative hemiparesis following tonsillectomy.

We report a rare complication following a routine elective tonsillectomy. A 32-year-old woman woke up from general anaesthesia with left sided hemiparesis. She underwent extensive investigations, which were normal. At follow-up neurology clinic she was given a new diagnosis of hemiplegic migraine and commenced on treatment. This case draws attention to a rare cause of postoperative hemiparesis. Hemiplegic migraine is a differential diagnosis for postoperative motor deficit after exclusion of an acute neurological or metabolic event.

Rising to the challenge: applying biofabrication approaches for better drug and chemical product development.

Many industrial sectors, from pharmaceuticals to consumer products, are required to provide data on their products to demonstrate their efficacy and that they are safe for patients, consumers and the environment. This period of testing typically requires the use of animal models, the validity of which has been called into question due to the high rates of attrition across many industries. There is increasing recognition of the limitations of animal models and demands for safety and efficacy testing paradigms which embrace the latest technological advances and knowledge of human biology. This perspective article highlights the potential for biofabrication approaches (encompassing bioprinting and bioassembly strategies) to meet these needs and provides case studies from three different industry sectors to demonstrate the potential for new markets in the bioprinting community. We also present a series of recommendations to create a thriving bioprinting environment. One that operates at the forefront of science, technology and innovation to deliver improved decision-making tools for the more rapid development of medicines, agrichemicals, chemicals and consumer products, and which may reduce our reliance on animals.

Long-term impact of sewage sludge application on soil microbial biomass: An evaluation using meta-analysis.

The Long-Term Sludge Experiments (LTSE) began in 1994 as part of continuing research into the effects of sludge-borne heavy metals on soil fertility. The long-term effects of Zn, Cu, and Cd on soil microbial biomass carbon (Cmic) were monitored for 8 years (1997-2005) in sludge amended soils at nine UK field sites. To assess the statutory limits set by the UK Sludge (Use in Agriculture) Regulations the experimental data has been reviewed using the statistical methods of meta-analysis. Previous LTSE studies have focused predominantly on statistical significance rather than effect size, whereas meta-analysis focuses on the magnitude and direction of an effect, i.e. the practical significance, rather than its statistical significance. The results presented here show that significant decreases in Cmic have occurred in soils where the total concentrations of Zn and Cu fall below the current UK statutory limits. For soils receiving sewage sludge predominantly contaminated with Zn, decreases of approximately 7-11% were observed at concentrations below the UK statutory limit. The effect of Zn appeared to increase over time, with increasingly greater decreases in Cmic observed over a period of 8 years. This may be due to an interactive effect between Zn and confounding Cu contamination which has augmented the bioavailability of these metals over time. Similar decreases (7-12%) in Cmic were observed in soils receiving sewage sludge predominantly contaminated with Cu; however, Cmic appeared to show signs of recovery after a period of 6 years. Application of sewage sludge predominantly contaminated with Cd appeared to have no effect on Cmic at concentrations below the current UK statutory limit.