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Background: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS)., Methods: The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project., Results: FCS was relatively common in non-Europeans and those with parental consanguinity ( P <0.001 for both). LPL variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; P =0.001), recurrent pancreatitis (92% versus 63%; P <0.001), unexplained abdominal pain (84% versus 52%; P <0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; P <0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; P <0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS ( P <0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS ( P =0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS., Conclusions: The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS., Competing Interests: H. Soran received personal fees from Amgen, Akcea, Synageva, Napp, Novartis, Takeda, Sanofi, Pfizer, and Kowa and research grants and donations from Akcea, Pfizer, Merck Sharp & Dohme, Amgen, Genzyme-Sanofi, Synageva, Amryt, Synageva, and Alexion. A.S. Wierzbicki is a site investigator on trials from Akcea and Regeneron; received royalties from Elsevier for a book on familial chylomicronemia syndrome; and is a board member for the Familial Hyperlipidaemia group, Europe. D. Datta received honoraria for advisory board from Swedish Orphan Biovitrum. N. Forrester received honoraria for presentations from SOBI. Y. Teoh received speakers fee from Daiichi Sankyo and Amarin. P. Downie received honoraria from SOBI, Novartis, Amgen, and Daiichi Sankyo. R.A. Hegele received consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Arrowhead, HLS Therapeutics, Pfizer, Novartis, Regeneron, Sanofi, and UltraGenyx. The other authors report no conflicts.

This study determines the functional role of the plant ultraviolet-B radiation (UV-B) photoreceptor, UV RESISTANCE LOCUS 8 (UVR8) under natural conditions using a large-scale 'synchronized-genetic-perturbation-field-experiment'. Laboratory experiments have demonstrated a role for UVR8 in UV-B responses but do not reflect the complexity of outdoor conditions where 'genotype × environment' interactions can mask laboratory-observed responses. Arabidopsis thaliana knockout mutant, uvr8-7, and the corresponding Wassilewskija wild type, were sown outdoors on the same date at 21 locations across Europe, ranging from 39°N to 67°N latitude. Growth and climatic data were monitored until bolting. At the onset of bolting, rosette size, dry weight, and phenolics and glucosinolates were quantified. The uvr8-7 mutant developed a larger rosette and contained less kaempferol glycosides, quercetin glycosides and hydroxycinnamic acid derivatives than the wild type across all locations, demonstrating a role for UVR8 under field conditions. UV effects on rosette size and kaempferol glycoside content were UVR8 dependent, but independent of latitude. In contrast, differences between wild type and uvr8-7 in total quercetin glycosides, and the quercetin-to-kaempferol ratio decreased with increasing latitude, that is, a more variable UV response. Thus, the large-scale synchronized approach applied demonstrates a location-dependent functional role of UVR8 under natural conditions., (© 2024 The Author(s). Plant, Cell & Environment published by John Wiley & Sons Ltd.)

The US Environmental Protection Agency (USEPA) considers sediment toxicity tests as conditional registration requirements for pesticides with soil Kd ≥50 L/kg-solid, Koc ≥1000 L/kg-organic carbon, or log Kow ≥3. The hydrophobicity of these compounds often necessitates use of solvents to ensure accurate and homogeneous dosing of spiked-sediment studies. For sediment tests, a volatile solvent (e.g., acetone) is generally used as a transient carrier. Due to low water solubility, test material is dissolved in a volatile solvent to create stock solutions. A measured aliquot of stock solution is then mixed with sand substrate, after which the solvent is evaporated. This spiking process results in negligible solvent exposure to organisms. In 2016, USEPA released final ecotoxicity test guidelines for subchronic freshwater (850.1735) and marine (850.1740) sediment test. These methods provide an option for conducting experiments with only a solvent control and no negative control. To adopt this testing strategy, functional equivalency between the negative and solvent control must be demonstrated. These test guidelines describe specific factors that should be considered for evaluating functional equivalency, including (a) the concentration of solvent in the test sediment after evaporation, (b) the levels of solvent that are known to affect organism health, (c) the known impurities in the solvent and their potential impact on organism health, and (d) the historical organism performance of solvent versus negative controls. Our analysis considers these factors and overall supports the elimination of the negative control requirement because this change is unlikely to impact the robustness or interpretability of spiked-sediment toxicity tests. Environ Toxicol Chem 2024;43:1740-1746. © 2023 CropLife America. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2023 CropLife America. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Bioaccumulation predictions can be substantially improved by combining in vitro metabolic rate measurements derived from rainbow trout hepatocytes and/or hepatic S9 fractions with quantitative structure-activity relationship (QSAR) modeling approaches. Compared with in vivo testing guidelines Organisation for Economic Co-operation and Development (OECD) 305 and Office of Chemical Safety and Pollution Prevention (OCSPP; an office of the US Environmental Protection Agency) 850.1730, the recently adopted OECD test guidelines 319A and 319B are in vitro approaches that have the potential to provide a time- and cost-efficient, humane solution, reducing animal use while addressing uncertainties in bioaccumulation across species. The present study compares the hepatic clearance of the S9 subcellular fraction of rainbow trout, bluegill, common carp, fathead minnow, and largemouth bass, discerning potential differences in metabolism between different warm- and cold-water species. With refinements to the in vitro metabolic S9 assay for high-throughput analysis, we measured in vitro clearance rates of seven chemicals crossing multiple classes of chemistry and modes of action. We confirmed that data from rainbow trout liver S9 fraction metabolic rates can be utilized to predict rainbow trout bioconcentration factors using an in vitro to in vivo extrapolation model, as intended in the OECD 319B applicability domain per the bioaccumulation prediction. Also, we determined that OECD 319B can be applied to other species, modified according to their habitat, adaptations to feeding behavior, and environmental conditions (e.g., temperature). Once toxicokinetics for each species is better understood and appropriate models are developed, this method can be an excellent tool to determine hepatic clearance and potential bioaccumulation across species. The present study could be leveraged prior to or in place of initiating in vivo bioconcentration studies, thus optimizing selection of appropriate fish species. Environ Toxicol Chem 2024;43:1390-1405. © 2024 SETAC., (© 2024 SETAC.)

The Xenopus Eleutheroembryonic Thyroid Assay (XETA) was recently published as an OECD Test Guideline for detecting chemicals acting on the thyroid axis. However, the OECD validation did not cover all mechanisms that can potentially be detected by the XETA. This study was therefore initiated to investigate and consolidate the applicability domain of the XETA regarding the following mechanisms: thyroid hormone receptor (THR) agonism, sodium-iodide symporter (NIS) inhibition, thyroperoxidase (TPO) inhibition, deiodinase (DIO) inhibition, glucocorticoid receptor (GR) agonism, and uridine 5'-diphospho-glucuronosyltransferase (UDPGT) induction. In total, 22 chemicals identified as thyroid-active or -inactive in Amphibian Metamorphosis Assays (AMAs) were tested using the XETA OECD Test Guideline. The comparison showed that both assays are highly concordant in identifying chemicals with mechanisms of action related to THR agonism, DIO inhibition, and GR agonism. They also consistently identified the UDPGT inducers as thyroid inactive. NIS inhibition, investigated using sodium perchlorate, was not detected in the XETA. TPO inhibition requires further mechanistic investigations as the reference chemicals tested resulted in opposing response directions in the XETA and AMA. This study contributes refining the applicability domain of the XETA, thereby helping to clarify the conditions where it can be used as an ethical alternative to the AMA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David Du Pasquier, Benoit Salinier, Gregory Lemkine, Barbara Robin-Duchesne reports financial support was provided by CropLife Europe. Laurent Lagadic reports a relationship with Bayer CropScience AG that includes: employment. This work was supported by CropLife Europe as a Company Investment Project and research and development funds from Corteva Agriscience USA. The employment affiliation of the authors is listed on the cover page. BRD, BS, DDP and GL are affiliated to Laboratoire WatchFrog, developer of the Xenopus Eleutheroembryonic Thyroid Assay (XETA) and coordinator of the validation of OECD TG 248. AJ, JL, JRW, KKC, LL, LW and OK are affiliated to companies that manufacture agrochemicals, some of which having been used in the present study. There are no other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Prognosis and management differ between familial chylomicronaemia syndrome (FCS), a rare autosomal recessive disorder, and multifactorial chylomicronaemia syndrome (MCS) or severe mixed hyperlipidaemia. A clinical scoring tool to differentiate these conditions has been devised but not been validated in other populations. The objective of this study was to validate this score in the UK population and identify any additional factors that might improve it., Methods: A retrospective validation study was conducted using data from 151 patients comprising 75 FCS and 76 MCS patients. All participants had undergone genetic testing for genes implicated in FCS. Validation was performed by standard methods. Additional variables were identified from clinical data by logistic regression analysis., Results: At the recommended FCS score threshold ≥10 points, the sensitivity and specificity of the score in the UK population were 96% and 75%, respectively. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.88 (95% CI 0.83-0.94, p < 0.001). This study identified non-European (predominantly South Asian) ethnicity, parental consanguinity, body mass index (BMI) < 25 kg/m 2 , and recurrent pancreatitis as additional positive predictors, while BMI >30 kg/m 2 was found to be a negative predictor for FCS. However, inclusion of additional FCS predictors had no significant impact on performance of standard FCS score., Conclusions: Our study validates the FCS score in the UK population to distinguish FCS from MCS. While additional FCS predictors were identified, they did not improve further the score diagnostic performance., Competing Interests: Declaration of competing interest HS: Received personal fees from Amgen, Akcea, Synageva, NAPP, Novartis, Takeda, Sanofi, Pfizer, SOBI and Kowa and research grants and donations from Akcea, Pfizer, MSD, Amgen, Genzyme-Sanofi, Synageva, Amryt, Synageva and Alexion. ASW: Received grants from Akcea, Regeneron; Royalties from Elsevier and is a board member for familial hyperlipidaemia group, Europe. DD: Received honoraria for advisory boards from SOBI. NF: Received honoraria for presentations from SOBI. YT: Received speakers fee from Daiichi Sankyo and Amarin. PD: Received honoraria from SOBI, NOVARTIS, AMGEN and Daiichi Sankyo. PM: Participated on a Data Safety Monitoring Board and Advisory Board for Ionis, AKCEA, AMRYT, AMARIN, Ultragenix AG: received research grants from AMGEN, SANOFI, AMRYT, ULTRAGENYX, Consulting fee or honoraria from AMGEN, SANOFI, AMRYT, ULTRAGENYX, NOVARTIS, AKCEA, SERVIER. BB, SK, CD, AJ, FJ, MM, HD, PH, MM, AA, DO, PND: None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs., Methods: An observational study in an area representing one-fifth of England., Results: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF., Conclusion: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Importance: Spanish-speaking participants are underrepresented in clinical trials, limiting study generalizability and contributing to ongoing health inequity. The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial intentionally included Spanish-speaking participants., Objective: To describe trial participation and compare clinical and patient-reported outcomes among Spanish-speaking and English-speaking participants with acute appendicitis randomized to antibiotics., Design, Setting, and Participants: This study is a secondary analysis of the CODA trial, a pragmatic randomized trial comparing antibiotic therapy with appendectomy in adult patients with imaging-confirmed appendicitis enrolled at 25 centers across the US from May 1, 2016, to February 28, 2020. The trial was conducted in English and Spanish. All 776 participants randomized to antibiotics are included in this analysis. The data were analyzed from November 15, 2021, through August 24, 2022., Intervention: Randomization to a 10-day course of antibiotics or appendectomy., Main Outcomes and Measures: Trial participation, European Quality of Life-5 Dimensions (EQ-5D) questionnaire scores (higher scores indicating a better health status), rate of appendectomy, treatment satisfaction, decisional regret, and days of work missed. Outcomes are also reported for a subset of participants that were recruited from the 5 sites with a large proportion of Spanish-speaking participants., Results: Among eligible patients 476 of 1050 Spanish speakers (45%) and 1076 of 3982 of English speakers (27%) consented, comprising the 1552 participants who underwent 1:1 randomization (mean age, 38.0 years; 976 male [63%]). Of the 776 participants randomized to antibiotics, 238 were Spanish speaking (31%). Among Spanish speakers randomized to antibiotics, the rate of appendectomy was 22% (95% CI, 17%-28%) at 30 days and 45% (95% CI, 38%-52%) at 1 year, while in English speakers, these rates were 20% (95% CI, 16%-23%) at 30 days and 42% (95% CI 38%-47%) at 1 year. Mean EQ-5D scores were 0.93 (95% CI, 0.92-0.95) among Spanish speakers and 0.92 (95% CI, 0.91-0.93) among English speakers. Symptom resolution at 30 days was reported by 68% (95% CI, 61%-74%) of Spanish speakers and 69% (95% CI, 64%-73%) of English speakers. Spanish speakers missed 6.69 (95% CI, 5.51-7.87) days of work on average, while English speakers missed 3.76 (95% CI, 3.20-4.32) days. Presentation to the emergency department or urgent care, hospitalization, treatment dissatisfaction, and decisional regret were low for both groups., Conclusions and Relevance: A high proportion of Spanish speakers participated in the CODA trial. Clinical and most patient-reported outcomes were similar for English- and Spanish-speaking participants treated with antibiotics. Spanish speakers reported more days of missed work., Trial Registration: ClinicalTrials.gov Identifier: NCT02800785.

Background and Aims: The VOL4002 study assessed the efficacy and safety of volanesorsen in 22 adults with genetically confirmed familial chylomicronaemia syndrome (FCS) treated in the UK Early Access to Medicines Scheme (EAMS), with ("prior exposure") or without ("treatment naive") previous treatment in the APPROACH and/or APPROACH-OLE volanesorsen phase 3 studies., Methods: Data collection focused on triglyceride (TG) levels, platelet counts and pancreatitis events. Pancreatitis incidence during volanesorsen treatment was compared against the 5-year period preceding volanesorsen exposure. Volanesorsen 285 mg was self-administered subcutaneously once every 2 weeks., Results: Individual patient volanesorsen exposure ranged from 6 to 51 months (total cumulative exposure, 589 months). Among treatment-naive patients (n = 12), volanesorsen treatment resulted in an averaged median 52% reduction (-10.6 mmol/L) from baseline (26.4 mmol/L) in TG levels at 3 months, which were maintained through time points over 15 months of treatment (47%-55% reductions). Similarly, prior-exposure patients (n = 10) experienced a 51% reduction (-17.8 mmol/L) from pre-treatment baseline (28.0 mmol/L), with reductions of 10%-38% over 21 months of treatment. A comparison of pancreatitis event rates found a 74% reduction from the 5-year period before (one event/2.8 years) and during (one event/11.0 years) volanesorsen treatment. Platelet declines were consistent with observations in phase 3 clinical trials. No patient recorded a platelet count <50 × 10 9 /L., Conclusions: This longitudinal study supports the efficacy of volanesorsen in patients with FCS for lowering TG levels over treatment periods up to 51 months with no apparent safety signals related to increased duration of exposure., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:AJ has no conflicts of interest to declare.KP has no conflicts of interest to declare.ASW is a site investigator for clinical trials for Akcea, Amgen, Regeneron, and Sanofi.RR has no conflicts of interest to declare.MM has no conflicts of interest to declare. CD has no conflicts of interest to declare.AOF has no conflicts of interest to declare.HS has received research and education grants and honoraria from Akcea Therapeutics.FJ has no conflicts of interest to declare.IM has no conflicts of interest to declare.PD has received speaker fees and honoraria from Akcea Therapeutics for attendance at Advisory boards.PH has no conflicts of interest to declare.RJ was an employee of Akcea Therapeutics at the time the study was undertaken., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Familial chylomicronemia syndrome (FCS) is a rare, autosomal recessive genetic disorder characterized by a marked increase in plasma triglyceride (TG) levels and recurrent episodes of pancreatitis. The response to conventional TG-lowering therapies is suboptimal. Volanesorsen, an antisense oligonucleotide that targets hepatic apoC-III mRNA, has been shown to significantly reduce TGs in patients with FCS., Objective: To further evaluate the safety and efficacy of extended treatment with volanesorsen in patients with FCS., Methods: This phase 3 open-label extension study evaluated the efficacy and safety of extended treatment with volanesorsen in three groups of patients with FCS: Those who had previously received volanesorsen or placebo in the APPROACH and COMPASS studies, and treatment-naive patients not participating in either study. Key endpoints included change in fasting TG and other lipid measurements, and safety over 52 weeks., Results: Volanesorsen treatment resulted in sustained reductions in plasma TG levels in previously treated patients from the APPROACH and COMPASS studies. Volanesorsen-treated patients from the three populations studied had mean decreases in fasting plasma TGs from index study baseline to months 3, 6, 12 and 24 as follows: decreases of 48%, 55%, 50%, and 50%, respectively (APPROACH); decreases of 65%, 43%, 42%, and 66%, respectively (COMPASS); and decreases of 60%, 51%, 47%, and 46%, respectively (treatment-naive). Common adverse events were injection site reactions and platelet count decrease, consistent with previous studies., Conclusion: Extended open-label treatment with volanesorsen in patients with FCS resulted in sustained reductions of plasma TG levels and safety consistent with the index studies., Competing Interests: Declaration of Competing Interest JLW is a consultant to Ionis Pharmaceuticals and ST is an employee of Ionis Pharmaceuticals. JLW and ST are co-inventors and receive royalties from patents owned by the University of California, San Diego on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins. They are co-founders and have an equity interest in Oxitope, Inc and its affiliates (“Oxitope”) as well as in Kleanthi Diagnostics, LLC (“Kleanthi”). Although these relationships have been identified for conflict of interest management based on the overall scope of the project and its potential benefit to Oxitope and Kleanthi, the research findings included in this particular publication may not necessarily relate to the interests of Oxitope and Kleanthi. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. DG reports grants and personal fees from Ionis Pharmaceuticals during the conduct of the study; grants and personal fees from Allergan, Amgen, Amryt, Arrowhead, Eli Lilly, Novartis, NovoNordisk, Regeneron, and Sanofi outside the submitted work; grants from Acasti, Aegerion, Applied Therapeutics, AstraZeneca, Boehringer-Ingelheim, Ceapro, Dalcor, Esperion, Kowa, The Medicine Company, and Uniqure outside the submitted work; and personal fees from CRISPR Therapeutics, Saliogen, and Verve Therapeutics outside the submitted work. MA has received research grant support and lecturing fees from Alfasigma, Amgen, Amryt, Daiichi Sankyo, Ionis/Akcea, Novartis, Pfizer, Regeneron, and Sanofi. AJ has provided services to the following companies: Akcea, Amgen, Sanofi, and SOBI. HS received research and education grants and honoraria from Akcea Therapeutics, Alexion, Amryt, Synageva, Kowa, MSD, NAPP, Novartis, Pfizer, Sanofi, Synageva, and Takeda. IG-B has received personal honoraria from Aegerion, Akcea, Amarin, Amgen, Daiichi Sankyo, Novartis, Regeneron, and Sanofi; and nonfinancial support from Akcea, Amgen, and Sanofi. ESGS has received advisory board/lecturing fees, paid to institution, from: Amgen, Sanofi, NovoNordisk, AstraZeneca, Esperion, Daiichi-Sankyo, and Ionis/Akcea. No patents/stocks. VJA, LW, and SX are employees of Ionis Pharmaceuticals. RJ was an employee of Akcea Therapeutics at the time of the study and manuscript development and may own stock in Ionis Pharmaceuticals, parent company of Akcea Therapeutics., (Copyright © 2023 National Lipid Association. All rights reserved.)

A systematic review was conducted on the sensitivity of fish testing guidelines to detect the anti-androgenic activity of substances. Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) was used to investigate the conservation of the androgen receptor (AR) between humans and fish, and among fish species recommended in test guidelines. The AR is conserved between fish species and humans (i.e. ligand binding domain [LBD] homology ≥70%) and among the recommended fish species (LBD homology >85%). For model anti-androgens, we evaluated literature data on in vitro anti-androgenic activity in fish-specific receptor-based assays and changes in endpoints indicative of endocrine modulation from in vivo studies. Anti-androgenic activity was most consistently and reliably detected in in vitro and in vivo mechanistic studies with co-exposure to an androgen (spiggin in vitro assay, Rapid Androgen Disruption Activity Reporter [RADAR] Assay, and Androgenised Female Stickleback Screen). Regardless of study design (Fish Short-Term Reproduction Assay [FSTRA], Fish Sexual Development Test [FSDT], partial or full life-cycle tests), or endpoint (vitellogenin, secondary sexual characteristics, gonadal histopathology, sex ratio), there was no consistent evidence for detecting anti-androgenic activity in studies without androgen co-exposure, even for the most potent substances (while less potent substances may induce no (clear) response). Therefore, based on studies without androgen co-exposure (35 FSTRAs and 22 other studies), the other studies (including the FSDT) do not outperform the FSTRA for detecting potent anti-androgenic activity, which if suspected, would be best addressed with a RADAR assay. Overall, fish do not appear particularly sensitive to mammalian anti-androgens.

Wearing a cloth face mask has been shown to impair exercise performance; it is essential to understand the impact wearing a cloth face mask may have on cognitive performance. Participants completed two maximal cardiopulmonary exercise tests on a cycle ergometer (with and without a cloth face mask) with a concurrent cognitive task. Blood pressure, heart rate, oxygen saturation, perceived exertion, shortness of breath, accuracy, and reaction time were measured at rest, during each exercise stage, and following a 4-minute recovery period. The final sample included 35 adults (age = 26.1 ± 5.8 years; 12 female/23 male). Wearing a cloth face mask was associated with significant decreases in exercise duration (-2:00 ± 3:40 min, P  = 0.003), peak measures of maximal oxygen uptake (-818.9 ± 473.3 mL/min, -19.0 ± 48 mL·min -1 ·kg -1 , P  < 0.001), respiratory exchange ratio (-0.04 ± 0.08, P  = 0.005), minute ventilation (-36.9 ± 18 L/min), oxygen pulse (-3.9 ± 2.3, P  < 0.001), heart rate (-7.9 ± 12.6 bpm, P  < 0.001), oxygen saturation (-1.5 ± 2.8%, P  = 0.004), and blood lactate (-1.7 ± 2.5 mmol/L, P  < 0.001). While wearing a cloth face mask significantly impaired exercise performance during maximal exercise testing, cognitive performance was unaffected in this selected group of young, active adults., Competing Interests: This study was funded by the BSW Foundation. The authors report no conflicts of interest., (Copyright © 2023 Baylor University Medical Center.)

Importance: A patient's belief in the likely success of a treatment may influence outcomes, but this has been understudied in surgical trials., Objective: To examine the association between patients' baseline beliefs about the likelihood of treatment success with outcomes of antibiotics for appendicitis in the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial., Design, Setting, and Participants: This was a secondary analysis of the CODA randomized clinical trial. Participants from 25 US medical centers were enrolled between May 3, 2016, and February 5, 2020. Included in the analysis were participants with appendicitis who were randomly assigned to receive antibiotics in the CODA trial. After informed consent but before randomization, participants who were assigned to receive antibiotics responded to a baseline survey including a question about how successful they believed antibiotics could be in treating their appendicitis., Interventions: Participants were categorized based on baseline survey responses into 1 of 3 belief groups: unsuccessful/unsure, intermediate, and completely successful., Main Outcomes and Measures: Three outcomes were assigned at 30 days: (1) appendectomy, (2) high decisional regret or dissatisfaction with treatment, and (3) persistent signs and symptoms (abdominal pain, tenderness, fever, or chills). Outcomes were compared across groups using adjusted risk differences (aRDs), with propensity score adjustment for sociodemographic and clinical factors., Results: Of the 776 study participants who were assigned antibiotic treatment in CODA, a total of 425 (mean [SD] age, 38.5 [13.6] years; 277 male [65%]) completed the baseline belief survey before knowing their treatment assignment. Baseline beliefs were as follows: 22% of participants (92 of 415) had an unsuccessful/unsure response, 51% (212 of 415) had an intermediate response, and 27% (111 of 415) had a completely successful response. Compared with the unsuccessful/unsure group, those who believed antibiotics could be completely successful had a 13-percentage point lower risk of appendectomy (aRD, -13.49; 95% CI, -24.57 to -2.40). The aRD between those with intermediate vs unsuccessful/unsure beliefs was -5.68 (95% CI, -16.57 to 5.20). Compared with the unsuccessful/unsure group, those with intermediate beliefs had a lower risk of persistent signs and symptoms (aRD, -15.72; 95% CI, -29.71 to -1.72), with directionally similar results for the completely successful group (aRD, -15.14; 95% CI, -30.56 to 0.28)., Conclusions and Relevance: Positive patient beliefs about the likely success of antibiotics for appendicitis were associated with a lower risk of appendectomy and with resolution of signs and symptoms by 30 days. Pathways relating beliefs to outcomes and the potential modifiability of beliefs to improve outcomes merit further investigation., Trial Registration: ClinicalTrials.gov Identifier: NCT02800785.

Importance: In the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial, which found antibiotics to be noninferior, approximately half of participants randomized to receive antibiotics had outpatient management with hospital discharge within 24 hours. If outpatient management is safe, it could increase convenience and decrease health care use and costs., Objective: To assess the use and safety of outpatient management of acute appendicitis., Design, Setting, and Participants: This cohort study, which is a secondary analysis of the CODA trial, included 776 adults with imaging-confirmed appendicitis who received antibiotics at 25 US hospitals from May 1, 2016, to February 28, 2020., Exposures: Participants randomized to antibiotics (intravenous then oral) could be discharged from the emergency department based on clinician judgment and prespecified criteria (hemodynamically stable, afebrile, oral intake tolerated, pain controlled, and follow-up confirmed). Outpatient management and hospitalization were defined as discharge within or after 24 hours, respectively., Main Outcomes and Measures: Outcomes compared among patients receiving outpatient vs inpatient care included serious adverse events (SAEs), appendectomies, health care encounters, satisfaction, missed workdays at 7 days, and EuroQol 5-dimension (EQ-5D) score at 30 days. In addition, appendectomy incidence among outpatients and inpatients, unadjusted and adjusted for illness severity, was compared., Results: Among 776 antibiotic-randomized participants, 42 (5.4%) underwent appendectomy within 24 hours and 8 (1.0%) did not receive their first antibiotic dose within 24 hours, leaving 726 (93.6%) comprising the study population (median age, 36 years; range, 18-86 years; 462 [63.6%] male; 437 [60.2%] White). Of these participants, 335 (46.1%; site range, 0-89.2%) were discharged within 24 hours, and 391 (53.9%) were discharged after 24 hours. Over 7 days, SAEs occurred in 0.9 (95% CI, 0.2-2.6) per 100 outpatients and 1.3 (95% CI, 0.4-2.9) per 100 inpatients; in the appendicolith subgroup, SAEs occurred in 2.3 (95% CI, 0.3-8.2) per 100 outpatients vs 2.8 (95% CI, 0.6-7.9) per 100 inpatients. During this period, appendectomy occurred in 9.9% (95% CI, 6.9%-13.7%) of outpatients and 14.1% (95% CI, 10.8%-18.0%) of inpatients; adjusted analysis demonstrated a similar difference in incidence (-4.0 percentage points; 95% CI, -8.7 to 0.6). At 30 days, appendectomies occurred in 12.6% (95% CI, 9.1%-16.7%) of outpatients and 19.0% (95% CI, 15.1%-23.4%) of inpatients. Outpatients missed fewer workdays (2.6 days; 95% CI, 2.3-2.9 days) than did inpatients (3.8 days; 95% CI, 3.4-4.3 days) and had similar frequency of return health care visits and high satisfaction and EQ-5D scores., Conclusions and Relevance: These findings support that outpatient antibiotic management is safe for selected adults with acute appendicitis, with no greater risk of complications or appendectomy than hospital care, and should be included in shared decision-making discussions of patient preferences for outcomes associated with nonoperative and operative care., Trial Registration: ClinicalTrials.gov Identifier: NCT02800785.

Importance: For adults with appendicitis, several randomized clinical trials have demonstrated that antibiotics are an effective alternative to appendectomy. However, it remains unknown how the characteristics of patients in such trials compare with those of patients who select their treatment and whether outcomes differ., Objective: To compare participants in the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) randomized clinical trial (RCT) with a parallel cohort study of participants who declined randomization and self-selected treatment., Design, Setting, and Participants: The CODA trial was conducted in 25 US medical centers. Participants were enrolled between May 3, 2016, and February 5, 2020; all participants were eligible for at least 1 year of follow-up, with all follow-up ending in 2021. The randomized cohort included 1094 adults with appendicitis; the self-selection cohort included patients who declined participation in the randomized group, of whom 253 selected appendectomy and 257 selected antibiotics. In this secondary analysis, characteristics and outcomes in both self-selection and randomized cohorts are described with an exploratory analysis of cohort status and receipt of appendectomy., Interventions: Appendectomy vs antibiotics., Main Outcomes and Measures: Characteristics among participants randomized to either appendectomy or antibiotics were compared with those of participants who selected their own treatment., Results: Clinical characteristics were similar across the self-selection cohort (510 patients; mean age, 35.8 years [95% CI, 34.5-37.1]; 218 female [43%; 95% CI, 39%-47%]) and the randomized group (1094 patients; mean age, 38.2 years [95% CI, 37.4-39.0]; 386 female [35%; 95% CI, 33%-38%]). Compared with the randomized group, those in the self-selection cohort were less often Spanish speaking (n = 99 [19%; 95% CI, 16%-23%] vs n = 336 [31%; 95% CI, 28%-34%]), reported more formal education (some college or more, n = 355 [72%; 95% CI, 68%-76%] vs n = 674 [63%; 95% CI, 60%-65%]), and more often had commercial insurance (n = 259 [53%; 95% CI, 48%-57%] vs n = 486 [45%; 95% CI, 42%-48%]). Most outcomes were similar between the self-selection and randomized cohorts. The number of patients undergoing appendectomy by 30 days was 38 (15.3%; 95% CI, 10.7%-19.7%) among those selecting antibiotics and 155 (19.2%; 95% CI, 15.9%-22.5%) in those who were randomized to antibiotics (difference, 3.9%; 95% CI, -1.7% to 9.5%). Differences in the rate of appendectomy were primarily observed in the non-appendicolith subgroup., Conclusions and Relevance: This secondary analysis of the CODA RCT found substantially similar outcomes across the randomized and self-selection cohorts, suggesting that the randomized trial results are generalizable to the community at large., Trial Registration: ClinicalTrials.gov Identifier: NCT02800785.

Objectives: To (1) determine if wearing a cloth face mask significantly affected exercise performance and associated physiological responses, and (2) describe perceptual measures of effort and participants' experiences while wearing a face mask during a maximal treadmill test., Methods: Randomised controlled trial of healthy adults aged 18-29 years. Participants completed two (with and without a cloth face mask) maximal cardiopulmonary exercise tests (CPETs) on a treadmill following the Bruce protocol. Blood pressure, heart rate, oxygen saturation, exertion and shortness of breath were measured. Descriptive data and physical activity history were collected pretrial; perceptions of wearing face masks and experiential data were gathered immediately following the masked trial., Results: The final sample included 31 adults (age=23.2±3.1 years; 14 women/17 men). Data indicated that wearing a cloth face mask led to a significant reduction in exercise time (-01:39±01:19 min/sec, p<0.001), maximal oxygen consumption (VO 2 max) (-818±552 mL/min, p<0.001), minute ventilation (-45.2±20.3 L/min), maximal heart rate (-8.4±17.0 beats per minute, p<0.01) and increased dyspnoea (1.7±2.9, p<0.001). Our data also suggest that differences in SpO 2 and rating of perceived exertion existed between the different stages of the CPET as participant's exercise intensity increased. No significant differences were found between conditions after the 7-minute recovery period., Conclusion: Cloth face masks led to a 14% reduction in exercise time and 29% decrease in VO 2 max, attributed to perceived discomfort associated with mask-wearing. Compared with no mask, participants reported feeling increasingly short of breath and claustrophobic at higher exercise intensities while wearing a cloth face mask. Coaches, trainers and athletes should consider modifying the frequency, intensity, time and type of exercise when wearing a cloth face mask., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Case: A 31-year-old woman suffered a close-range, high-energy .30-rifle gunshot wound to her right ilium and sacrum resulting in an unstable pelvic ring injury with significant internal soft-tissue damage and bone loss. Given the limited amount of literature for managing this rare clinical scenario in a civilian setting, we described our protocol used on this patient to achieve a safe and effective result., Conclusions: We present a civilian-inflicted high-velocity pelvic gunshot injury at close range. Although the patient had extensive pelvic bone loss and soft-tissue damage, she had excellent clinical results at 18-month follow-up after delayed posterior sacral bridge plating. Proper soft-tissue management and posterior sacral plating may yield good results for management of this type of injury., Competing Interests: Disclosure: ptThe Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B700)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Owing to several key attributes, diamond is an attractive candidate material for neural interfacing electrodes. The emergence of additive-manufacturing (AM) of diamond-based materials has addressed multiple challenges associated with the fabrication of diamond electrodes using the conventional chemical vapor deposition (CVD) approach. Unlike the CVD approach, AM methods have enabled the deposition of three-dimensional diamond-based material at room temperature. This work demonstrates the feasibility of using laser metal deposition to fabricate diamond-titanium hybrid electrodes for neuronal interfacing. In addition to exhibiting a high electrochemical capacitance of 1.1 mF cm -2 and a low electrochemical impedance of 1 kΩ cm 2 at 1 kHz in physiological saline, these electrodes exhibit a high degree of biocompatibility assessed in vitro using cortical neurons. Furthermore, surface characterization methods show the presence of an oxygen-rich mixed-phase diamond-titanium surface along the grain boundaries. Overall, we demonstrated that our unique approach facilitates printing biocompatible titanium-diamond site-specific coating-free conductive hybrid surfaces using AM, which paves the way to printing customized electrodes and interfacing implantable medical devices.

Importance: Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed., Objective: To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19., Design, Setting, and Participants: This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients., Interventions: Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237)., Main Outcomes and Measures: The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality., Results: Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09])., Conclusions and Relevance: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults., Trial Registration: ClinicalTrials.gov: NCT04332991.

Diamond-based implant materials make up an emerging research area where the materials could be prepared to promote cellular functions, decrease bacteria attachment, and be suitable for potential in situ imaging. Up until now, diamond implants have been fabricated using coating technologies or embedding diamond nanoparticles in polymer matrices. Here we demonstrated a method of manufacturing diamond implants using laser cladding technology to 3D print a composite of diamond and fused titanium material. Using this method, we could prepare composite scaffolds of up to 50% diamond, which has never been achieved before. We next investigated the interfacial properties of these scaffolds for potential applications in implants. The addition of diamond to the biomaterial results in a 30% decrease in the water contact angle, making the scaffolds more hydrophilic and improving cellular adhesion and proliferation.

The aim of this review and discussion paper is to advance the debate on competence in nursing, simulation education, and literacy in simulation education pedagogy. Building on our previous patient-safety critical translational research work on drug dosage calculation-competence modelling, and safeMedicate ® virtual learning and diagnostic assessment environment design, we introduce three new concepts. First, we re-conceptualise the cognitive and physical modalities of a theory-practice gap, created by the traditional organisation of health professional education practice. Second, that simulated clinical environments occupy the liminal spaces between the ordered, symbolic and abstract world of the classroom, and the situated, messy world of clinical healthcare practice. Third, technology-enhanced boundary objects (TEBOs) function as simulation pedagogy modalities that (a) support students' transition across the liminal space and boundaries between classroom and practice setting, and (b) support competence development and integration in nursing. We use a constructivist-based clinical simulation education model as a guiding pedagogical framework for applying TEBOs and an integrated nursing competence model. The e-version of the paper has embedded animation and illustrative video content to demonstrate these constructivist principles, using technology and computer animation to make complex education ideas accessible to experienced educators and clinicians, early-stage educators, and nursing and healthcare students., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Familial chylomicronemia syndrome (FCS) is an ultra-rare phenotype that is usually caused by biallelic mutations in the LPL gene encoding lipoprotein lipase, or less often in APOC2, APOA5, LMF1, or GPIHBP1 genes encoding cofactors or interacting proteins., Objectives: We evaluated baseline phenotypes among FCS participants in a phase 3 randomized placebo-controlled trial of volanesorsen (NCT02211209)., Methods: Baseline clinical, fasting, and postfat load metabolic markers were assessed. Targeted next-generation DNA sequencing plus custom bioinformatics was used to genotype subjects., Results: Among 52 FCS individuals, 41 had biallelic LPL gene mutations (LPL-FCS patients): 82%, 7%, and 11% were missense, nonsense, and splicing variants, respectively. Eleven individuals had non-LPL-FCS; 2 had mutations in APOA5, 5 in GPIHBP1, and 1 each in LMF1 and APOC2 genes, respectively. Two other individuals were double heterozygotes, each with 1 normal LPL allele. All subjects had extremely high triglycerides (TGs) and chylomicrons, but very low levels of other lipoproteins. Compared with LPL-FCS individuals, non-LPL-FCS individuals were very similar for most traits, but had significantly higher postheparin LPL activity, higher 4-hour postprandial insulin and C-peptide levels; and higher low-density lipoprotein cholesterol levels. In non-LPL-FCS individuals compared to those with LPL-FCS, there were also nonsignificant trends toward lower levels of total and chylomicron TGs, lower 4-hour postprandial chylomicron TG levels, and higher very-low-density lipoprotein TG levels., Conclusion: Thus, LPL FCS and non-LPL FCS are largely phenotypically similar. However, LPL FCS patients have lower postheparin LPL activity and a trend toward higher TGs, whereas low-density lipoprotein cholesterol was higher in non-LPL-FCS patients., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Objectives: Psychological morbidities after injury [eg, posttraumatic stress disorder (PTSD) and depression] are increasingly recognized as a significant determinant of overall outcome. Traumatic brain injury (TBI) negatively impacts outcomes of patients with orthopaedic injury, but the association of concurrent TBI, orthopaedic injury, and symptoms of PTSD and depression has not been examined. This study's objective was to examine symptoms of PTSD and depression in patients with orthopaedic trauma with and without TBI., Design: Longitudinal prospective cohort study., Setting: Urban Level I Trauma Center in the Southwest United States., Patients/participants: Orthopaedic trauma patients older than 18 years admitted for ≥24 hours., Main Outcome Measurements: Questionnaires examining demographics, injury-related variables, PTSD, and depression were administered during hospitalization and 3, 6, and 12 months later. Orthopaedic injury and TBI were determined based on ICD-9 codes. Generalized linear models determined whether PTSD and depression at follow-up were associated with TBI., Results: Of the total sample (N = 214), 44 (21%) sustained a TBI. Those with TBI had higher rates of PTSD symptoms, 12 months postinjury (P = 0.04). The TBI group also had higher rates of depressive symptoms, 6 months postinjury (P = 0.038)., Conclusions: Having a TBI in addition to orthopaedic injury was associated with significantly higher rates of PTSD at 12 months and depression at 6 months postinjury. This suggests that sustaining a TBI in addition to orthopaedic injury places patients at a higher risk for negative psychological outcomes. The findings of this study may help clinicians to identify patients who are in need for psychological screening and could potentially benefit from intervention., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background Ethylene glycol is a highly toxic compound found in various household products. Cases of poisoning are rare but may be fatal unless diagnosed and treated promptly. Early recognition of poisoning is critical for the management and recovery of patients. Indirect testing is not specific for the presence of ethylene glycol. Therefore, urgent and accurate measurement should be sought if ingestion is suspected in order to determine the need for treatment with an antidote. Here, we present the validation of an automated assay for measurement of ethylene glycol on an Abbott Architect using a commercially available kit (Catachem). Methods Analytical parameters of imprecision, linearity, stability and bias were determined using spiked human plasma samples processed on both the Catachem assay and on an in-house gas chromatography-mass spectrometry method. Interference was assessed using samples collected into a variety of sample collection tubes and spiked with a number of alcohols. Results Excellent agreement was observed between the two methodologies with the enzymatic assay demonstrating linearity and precision across the relevant clinical range (50-3000 mg/L). In addition, the Catachem assay displayed no interference from a number of different sample tubes and alcohols. However, propylene glycol interference was observed at concentrations associated with excessive use (>1 g/L) and 2,3-butanediol interference observed at concentrations associated with butanone ingestion. Inspection of the enzymatic reaction profile was found to differentiate between alcohols. Conclusions This automated assay is suitable for the diagnosis of ethylene glycol poisoning and is now in routine use, enabling the laboratory to provide a rapid 24 h service with support by gas chromatography-mass spectrometry as necessary.

Background: Despite the recognition of the importance of diagnosing dysglycaemia in patients with acute coronary syndrome (ACS) there remains a lack of consensus on the best screening modality. Our primary aims were to determine the prevalence of undiagnosed dysglycaemia and to compare the OGTT and HbA1c criteria for diagnosis of T2DM in patients admitted to hospital with ACS at baseline and at 3-months. We also aimed to investigate the role of a screening algorithm and a predictor score to define glucose tolerance in this population., Methods: A prospective study in which patients admitted with ACS to two UK teaching hospitals were assessed at baseline and 3 months follow-up., Results: The prevalence of diabetes at baseline was 20% and 16% based on OGTT and HbA1c criteria respectively. Forty three (43) % of the patients with T2DM based on OGTT would have been missed by the HbA1c criteria at baseline. Our screening algorithm identified 87% of patients with T2DM diagnosed with OGTT. Diabetes Predictor score had better sensitivity (>80%) and negative predictive value (>90%) compared to HbA1c criteria. Two thirds of participants with IGS and a third with T2DM changed their glycaemic status at 3 months., Conclusions: Only 48% of the patients admitted with ACS had normo-glycaemia based on OGTT. OGTT and HbA1c identified two different populations of patients with dysglycaemia with the HbA1c criteria missing almost half the patients with T2DM based on OGTT. Compared to HbA1c criteria our diabetes algorithm and diabetes predictor score had a better correlation with OGTT criteria.

Ongoing coastal development and the prospect of severe climate change impacts present pressing estuary management and governance challenges. Robust approaches must recognise the intertwined social and ecological vulnerabilities of estuaries. Here, a new governance and management framework is proposed that recognises the integrated social-ecological systems of estuaries so as to permit transformative adaptation to climate change within these systems. The framework lists stakeholders and identifies estuarine uses and values. Goals are categorised that are specific to ecosystems, private property, public infrastructure, and human communities. Systematic adaptation management strategies are proposed with conceptual examples and associated governance approaches. Contrasting case studies are used to illustrate the practical application of these ideas. The framework will assist estuary managers worldwide to achieve their goals, minimise maladaptative responses, better identify competing interests, reduce stakeholder conflict and exploit opportunities for appropriate ecosystem restoration and sustainable development., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Human factors research has suggested benefits of consistent teams yet no surgical team consistency measures have been established for teamwork improvement initiatives., Methods: Retrospective analysis was conducted of teams performing consecutive elective procedures of unilateral primary total knee and hip replacement between June 2008 and May 2010 at a large tertiary medical center. Surgeons who performed fewer than 50 cases of the procedures during the study period were excluded. A team was defined as consistent when its nurse and surgical technologist members were both among the three most frequent working with the surgeon during the study period. Odds ratios for prolonged operative time (in the longest quartile), prolonged hospital stay (longer than median), and 30-day all-cause readmissions were adjusted for patient characteristics (sex, age, comorbidity, American Society of Anesthesiology status), surgery characteristics (procedures, time of day), and surgeons., Results: Inconsistent teams performed 61% of the 1,923 cases with eight surgeons, each of which worked with a median of 43.5 (range, 28-58) nurses and 29 (range, 13-47) technologists. Inconsistent teams were associated with higher likelihood of prolonged operative time [odds ratio 1.52, 95% confidence interval (CI) 1.20-1.91], higher likelihood of prolonged hospital stay (odds ratio 1.51, 95% CI 1.23-1.86), and more readmissions (adjusted odds ratio 1.42, 95% CI 1.07-1.89)., Conclusions: Team consistency was an independent predictor of prolonged operative time, prolonged hospital stay, and 30-day hospital readmission in elective, primary, unilateral total knee, and hip replacement procedures, after adjusting for patient and surgery characteristics and surgeons.

The current and projected nurse workforce shortage has created significant pressure on health care organizations to examine their approach to managing talent. This includes the need for strategic development of new formal leaders. This article reports on a succession planning program for prospective nursing unit managers. Eight prospective management candidates participated in a Future Nursing Unit Managers program. The effectiveness of the program was measured through a comparison of pre- and postprogram surveys relating to participants' perception of personal managerial and leadership skills. Significant differences in scores from baseline to 6-month follow-up surveys were observed in the participants' confidence in undertaking the nursing unit manager role and in their management skills. Investment in structured programs to prepare nurses for leadership roles is strongly recommended as a management workforce strategy.

Objectives: This study sought to determine the clinical and biological significance of elevated cardiac troponin T (cTnT) in patients with neuromuscular diseases., Background: Practice guidelines regard cTnT and cardiac troponin I (cTnI) as equally sensitive and specific for the diagnosis of myocardial injury. Although cTnI is unique to myocardium, cTnT can be re-expressed in skeletal muscle in response to injury. The commercial cTnT assay is claimed to be cardiac specific., Methods: Fifty-two patients with 20 different types of acquired and inherited neuromuscular diseases underwent full clinical assessment, cardiac investigations, and measurements of serum cTnT, cTnI, creatine kinase (CK), creatine kinase myocardial band (CK-MB), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)., Results: Serial measurements (265 samples) in 25 initially hospitalized patients taken during a mean of 2.4 years showed persistent elevation of cTnT (median: 0.08 μg/l; interquartile range: 0.06 to 0.14 μg/l), CK (582 U/l; 303 to 3,662 U/l), and CK-MB (24 μg/l; 8 to 34 μg/l). In contrast, cTnI, measured using 2 sensitive assays, was persistently normal throughout the study in 22 patients. Electrocardiograms (ECGs) and echocardiograms were normal in 16 and 17 patients, respectively, and no serial changes were observed. Therapeutic interventions in patients with reversible myopathies normalized cTnT, CK, and CK-MB in unison. Single measurements in 27 ambulatory patients showed elevated CK (953 U/l; 562 to 1,320 U/l), CK-MB (18 μg/l; 11 to 28 μg/l), and cTnT (0.03 μg/l; 0.02 to 0.05 μg/l) in 21, 22, and 18 patients respectively. cTnI was abnormal in only 1 patient. NT-proBNP (41 pg/ml; 35 to 97 pg/ml) was normal in all but 2 patients. ECGs were normal in 15 patients. No patients with elevated cTnT, but with normal cTnI, had any cardiovascular events in either group during follow-up., Conclusions: Patients with a wide spectrum of neuromuscular diseases commonly have persistent elevation of cTnT and CK-MB in the absence of clinical and cTnI evidence of myocardial injury. Re-expressed cTnT in diseased skeletal muscle appears to be the source of the elevated cTnT detected in the circulation of these patients., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Glaucousness is described as the scattering effect of visible light from wax deposited on the cuticle of plant aerial organs. In wheat, two dominant genes lead to non-glaucous phenotypes: Inhibitor of wax 1 (Iw1) and Iw2. The molecular mechanisms and the exact extent (beyond visual assessment) by which these genes affect the composition and quantity of cuticular wax is unclear. To describe the Iw1 locus we used a genetic approach with detailed biochemical characterization of wax compounds. Using synteny and a large number of F2 gametes, Iw1 was fine-mapped to a sub-cM genetic interval on wheat chromosome arm 2BS, which includes a single collinear gene from the corresponding Brachypodium and rice physical maps. The major components of flag leaf and peduncle cuticular waxes included primary alcohols, β-diketones and n-alkanes. Small amounts of C19-C27 alkyl and methylalkylresorcinols that have not previously been described in wheat waxes were identified. Using six pairs of BC2 F3 near-isogenic lines, we show that Iw1 inhibits the formation of β- and hydroxy-β-diketones in the peduncle and flag leaf blade cuticles. This inhibitory effect is independent of genetic background or tissue, and is accompanied by minor but consistent increases in n-alkanes and C24 primary alcohols. No differences were found in cuticle thickness and carbon isotope discrimination in near-isogenic lines differing at Iw1., (© 2013 The Authors The Plant Journal © 2013 John Wiley & Sons Ltd.)

Introduction: Several observational studies suggest that statins modulate the pathophysiology of sepsis and may prevent its progression. The aim of this study was to determine if the acute administration of atorvastatin reduces sepsis progression in statin naïve patients hospitalized with sepsis., Methods: A single centre phase II randomized double-blind placebo-controlled trial. Patients with sepsis were randomized to atorvastatin 40 mg daily or placebo for the duration of their hospital stay up to a maximum of 28-days. The primary end-point was the rate of sepsis progressing to severe sepsis during hospitalization., Results: 100 patients were randomized, 49 to the treatment with atorvastatin and 51 to placebo. Patients in the atorvastatin group had a significantly lower conversion rate to severe sepsis compared to placebo (4% vs. 24% p = 0.007.), with a number needed to treat of 5. No significant difference in length of hospital stay, critical care unit admissions, 28-day and 12-month readmissions or mortality was observed. Plasma cholesterol and albumin creatinine ratios were significantly lower at day 4 in the atorvastatin group (p < 0.0001 and p = 0.049 respectively). No difference in adverse events between the two groups was observed (p = 0.238)., Conclusions: Acute administration of atorvastatin in patients with sepsis may prevent sepsis progression. Further multi-centre trials are required to verify these findings., Trial Registration: International Standard Randomized Control Trial Registry ISRCTN64637517.

Observations: A total of 13 intracerebral infusions were performed at approximately 1 month intervals in three NIH miniature pigs over the age range of 31-59 weeks. Pigs received azaperone and ketamine premedication to allow venous cannulation and propofol induction of anaesthesia. Anaesthesia was maintained with isoflurane throughout cranial surgery and MRI scanning. Physiological monitoring during surgery consisted of blood pressure, pulse, temperature and oxygen saturation monitoring, ECG and capnography. Analgesia consisted of meloxicam and morphine. However, during MRI scanning blood pressure and ECG monitoring had to be discontinued. Anaesthetized pigs underwent intermittent intraputamenal convection enhanced delivery (CED) of gadolinium with real-time magnetic resonance imaging. Progressive tachycardia was consistently observed in all pigs during CED with a mean ± SD maximum increase of 41 ± 22 beats minute(-1) from a baseline heart rate of 96 ± 9 minute(-1) . The heart rate remained elevated until recovery. A mean reduction in body temperature of 2.8 ± 0.6 °C from the start of anaesthesia was also observed during the period of MRI scanning. All pigs recovered from anaesthesia smoothly and heart rates returned to normal during the recovery period., Conclusions: Hypothermia is common in pigs undergoing this sedation and anaesthesia protocol. Convection enhanced delivery of drugs in healthy anaesthetized pigs may result in tachycardia., (© 2012 The Authors. Veterinary Anaesthesia and Analgesia. © 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.)

Beach erosion is likely to accelerate, driven by predicted consequences of climate change and coastal development. Erosion is increasingly combated by beach nourishment, adding sand to eroding shores. Because a range of engineering techniques exists to nourish beaches, and because these techniques differ in their environmental effects, assessments of ecological impacts need to be tailored and specific. Here we report on impacts and recovery of benthic invertebrates impacted by beach nourishment operations undertaken at Palm Beach (SE Queensland, Australia). Assessments are made based on a beyond-BACI design, where samples were taken once before nourishment and twice afterwards at the impact and two control sites. Because almost all of the sand was deposited on the upper beach and later moved with bulldozers down-shore, we specifically examined whether the effects of nourishment varied at different heights of the beach-a little-studied question which has management implications. Impacts on the fauna were massive on the upper and middle levels of the beach: samples collected two days after the conclusion of nourishment were entirely devoid of all invertebrate life ('azoic'), whereas weaker effects of nourishment were detectable on the lower shore. Recovery after five months also varied between shore levels. The sediment of the upper level near the dunes remained azoic, the fauna of the middle shore had recovered partially, and the lower level had recovered in most respects. These findings indicate that the height and position of sand placement are important. For example, rather than depositing fill sand on the intertidal beach, it could be placed in the shallow subtidal zone, followed by slow up-shore accretion driven by hydrodynamic forces. Alternatively, techniques that spread the fill sand in thin layers (to minimize mortality by burial) and leave unfilled intertidal refuge islands (to provide colonists) may minimize the ecological impacts of beach nourishment., (Copyright © 2012. Published by Elsevier B.V.)

Objectives: Dialectical behavioral therapy (DBT) has gained widespread popularity as a treatment for borderline personality disorder (BPD), and its efficacy has been demonstrated in several trials. The aim of this study was to evaluate the effectiveness of DBT delivered by staff with a level of training readily achievable in National Health Service care settings for individuals with a Cluster B personality disorder., Design: Randomized control trial methodology was used to compare DBT to treatment as usual (TAU)., Method: Forty-two participants entered the trial. Diagnostic and outcome measures were undertaken at assessment, at 6 months, and at 1 year. The clinical outcomes in routine evaluation--outcome measure (CORE-OM) were utilized as the primary outcome measure., Results: Both the DBT and TAU groups improved on the range of measures employed. The DBT group showed a slightly greater decrease in CORE-OM risk scores, suicidality, and post-traumatic stress disorder symptom severity. However, the TAU group showed comparable reductions in all measures and a larger decrease in para-suicidal behaviours and risk., Conclusions: DBT may be an effective treatment delivered by community outpatient services for individuals with a Cluster B personality disorder. Further studies are needed to consider the impact of experience and adherence to DBT in improving outcome., (©2011 The British Psychological Society.)

Ozone (O(3)) uptake by plants leads to an increase in reactive oxygen species (ROS) in the intercellular space of leaves and induces signalling processes reported to involve the membrane-bound heterotrimeric G-protein complex. Therefore, potential G-protein-mediated response mechanisms to O(3) were compared between Arabidopsis thaliana L. lines with null mutations in the α- and β-subunits (gpa1-4, agb1-2 and gpa1-4/agb1-2) and Col-0 wild-type plants. Plants were treated with a range of O(3) concentrations (5, 125, 175 and 300 nL L(-1)) for 1 and 2 d in controlled environment chambers. Transcript levels of GPA1, AGB1 and RGS1 transiently increased in Col-0 exposed to 125 nL L(-1) O(3) compared with the 5 nL L(-1) control treatment. However, silencing of α and β G-protein genes resulted in little alteration of many processes associated with O(3) injury, including the induction of ROS-signalling genes, increased leaf tissue ion leakage, decreased net photosynthesis and stomatal conductance, and increased peroxidase activity, especially in the leaf apoplast. These results indicated that many responses to O(3) stress at physiological levels were not detectably influenced by α and β G-proteins., (Published 2011. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To examine the efficacy and tolerability of rosuvastatin 5 mg at daily and non-daily dosing regimens., Research Design and Methods: A retrospective survey was conducted at nine primary, secondary and tertiary healthcare centres in the United Kingdom., Main Outcome Measures: Changes in lipid fractions from baseline values after more than 3 months' treatment., Results: A total of 325 patients were identified. These patients were aged 63 ± 10 years, 50% male and prescription was mostly for primary prevention of cardiovascular disease (CVD) (59%). Co-morbidities included: established CVD present in 41%, type 2 diabetes mellitus (15%), hypertension (74%) and smoking (9%). Adverse effects had been documented to simvastatin (75%) or atorvastatin (63%). A total of 289 patients (89%) tolerated rosuvastatin well and were still adherent after a median follow-up of 14.9 (3-79) months. The remainder (n = 36; 11%) discontinued the medication after median 5 months' treatment due to adverse effects. Efficacy was assessed in 224 patients who had adequate data. Baseline lipids were total cholesterol (TC) 7.41 ± 1.50 mmol/L, triglycerides (TG) 2.26 (range 0.36-18.4) mmol/L; high density lipoprotein cholesterol (HDL-C) 1.43 ± 0.47 mmol/L and low density lipoprotein cholesterol (LDL-C) 4.76 ± 1.38 mmol/L. Daily rosuvastatin (n = 134) reduced mean TC by 31%, TG 15% and LDL-C 43% (p < 0.001). Rosuvastatin 5 mg 2-3 times weekly (n = 79) reduced TC 26%, TG 16% and LDL-C 32% (p < 0.001). Weekly rosuvastatin (n = 11) reduced TC 17%, LDL-C by 23% (p < 0.001) but had no effect on TGs. Targets were attained in 17% of CHD-risk equivalent patients and 41% of primary prevention patients by National Cholesterol Education Program criteria and 27% and 68% using UK targets. No myositis or rhabdomyolysis was observed and alanine aminotransferase (ALT) and creatine kinase (CK) were similar to baseline., Conclusions: In this retrospective observational multicentre study, rosuvastatin 5 mg was found to be safe and biochemically effective either as daily or intermittent therapy in patients intolerant to other conventional statin regimens.

Graphene is a new nanomaterial with unusual and useful physical and chemical properties. However, in the form of nanoplatelets this new, emerging material could pose unusual risks to the respiratory system after inhalation exposure. The graphene-based nanoplatelets used in this study are commercially available and consist of several sheets of graphene (few-layer graphene). We first derived the respirability of graphene nanoplatelets (GP) from the basic principles of the aerodynamic behavior of plate-shaped particles which allowed us to calculate their aerodynamic diameter. This showed that the nanoplatelets, which were up to 25 μm in diameter, were respirable and so would deposit beyond the ciliated airways following inhalation. We therefore utilized models of pharyngeal aspiration and direct intrapleural installation of GP, as well as an in vitro model, to assess their inflammatory potential. These large but respirable GP were inflammogenic in both the lung and the pleural space. MIP-1α, MCP-1, MIP-2, IL-8, and IL-1β expression in the BAL, the pleural lavage, and cell culture supernatant from THP-1 macrophages were increased with GP exposure compared to controls but not with nanoparticulate carbon black (CB). In vitro, macrophages exposed to GP showed expression of IL-1β. This study highlights the importance of nanoplatelet form as a driver for in vivo and in vitro inflammogenicity by virtue of their respirable aerodynamic diameter, despite a considerable 2-dimensional size which leads to frustrated phagocytosis when they deposit in the distal lungs and macrophages attempt to phagocytose them. Our data suggest that nanoplatelets pose a novel nanohazard and structure-toxicity relationship in nanoparticle toxicology., (© 2011 American Chemical Society)

Objective: This study investigated and compared the prevalence of microalbuminuria and overt proteinuria and their determinants in a cohort of UK resident patients of white European or south Asian ethnicity with type 2 diabetes mellitus., Research Design and Methods: A total of 1978 patients, comprising 1486 of south Asian and 492 of white European ethnicity, in 25 general practices in Coventry and Birmingham inner city areas in England were studied in a cross-sectional study. Demographic and risk factor data were collected and presence of microalbuminuria and overt proteinuria assessed., Trial Registration Number: ISRCTN 38297969., Main Outcome Measures: Prevalences of microalbuminuria and overt proteinuria., Results: Urinary albumin:creatinine measurements were available for 1852 (94%) patients. The south Asian group had a lower prevalence of microalbuminuria, 19% vs. 23% and a higher prevalence of overt proteinuria, 8% vs. 3%, χ(2) = 15.85, 2df, P = 0.0004. In multiple logistic regression models, adjusted for confounding factors, significantly increased risk for the south Asian vs. white European patients for overt proteinuria was shown; OR (95% CI) 2.17 (1.05, 4.49), P = 0.0365. For microalbuminuria, an interaction effect for ethnicity and duration of diabetes suggested that risk for south Asian patients was lower in early years following diagnosis; OR for SA vs. WH at durations 0 and 1 year were 0.56 (0.37, 0.86) and 0.59 (0.39, 0.89) respectively. After 20 years' duration, OR = 1.40 (0.63, 3.08)., Limitations: Comparability of ethnicity defined groups; statistical methods controlled for differences between groups, but residual confounding may remain. Analyses are based on a single measure of albumin:creatinine ratio., Conclusions: There were significant differences between ethnicity groups in risk factor profiles and microalbuminuria and overt proteinuria outcomes. Whilst south Asian patients had no excess risk of microalbuminuria, the risk of overt proteinuria was elevated significantly, which might be explained by faster progression of renal dysfunction in patients of south Asian ethnicity.

Background/aim: People of south Asian origin have an excessive risk of morbidity and mortality from cardiovascular disease. We examined the effect of ethnicity on known risk factors and analysed the risk of cardiovascular events and mortality in UK south Asian and white Europeans patients with type 2 diabetes over a 2 year period., Methods: A total of 1486 south Asian (SA) and 492 white European (WE) subjects with type 2 diabetes were recruited from 25 general practices in Coventry and Birmingham, UK. Baseline data included clinical history, anthropometry and measurements of traditional risk factors - blood pressure, total cholesterol, HbA1c. Multiple linear regression models were used to examine ethnicity differences in individual risk factors. Ten-year cardiovascular risk was estimated using the Framingham and UKPDS equations. All subjects were followed up for 2 years. Cardiovascular events (CVD) and mortality between the two groups were compared., Trial Registration Number: ISRCTN 38297969., Findings: Significant differences were noted in risk profiles between both groups. After adjustment for clustering and confounding a significant ethnicity effect remained only for higher HbA1c (0.50 [0.22 to 0.77]; P = 0.0004) and lower HDL (-0.09 [-0.17 to -0.01]; P = 0.0266). Baseline CVD history was predictive of CVD events during follow-up for SA (P < 0.0001) but not WE (P = 0.189). Mean age at death was 66.8 (11.8) for SA vs. 74.2 (12.1) for WE, a difference of 7.4 years (95% CI 1.0 to 13.7 years), P = 0.023. The adjusted odds ratio of CVD event or death from CVD was greater but not significantly so in SA than in WE (OR 1.4 [0.9 to 2.2])., Limitations: Fewer events in both groups and short period of follow-up are key limitations. Longer follow-up is required to see if the observed differences between the ethnic groups persist., Conclusion: South Asian patients with type 2 diabetes in the UK have a higher cardiovascular risk and present with cardiovascular events at a significantly younger age than white Europeans. Enhanced and ethnicity specific targets and effective treatments are needed if these inequalities are to be reduced.

A case of percutaneous pulmonary valve implantation following a failed homograft in the pulmonary position is reported. A 16-year-old boy developed infective endocarditis of his pulmonary homograft, which was implanted four years earlier during a Ross procedure for congenital aortic stenosis. Following successful medical therapy, the boy was symptomatic due to pulmonary stenosis and regurgitation. A 22 mm Melody valve (Medtronic, USA) was successfully implanted percutaneously. His symptoms resolved and he was discharged home one day after the procedure. Echocardiography at the six-month follow-up demonstrated a normally functioning pulmonary valve. Percutaneous pulmonary valve replacement may make the Ross procedure a more attractive option for patients with aortic stenosis, particularly in the pediatric population.

Objective: Rats exposed to high airborne mass concentrations of low-solubility low-toxicity particles (LSLTP) have been reported to develop lung disease such as fibrosis and lung cancer. These particles are regulated on a mass basis in occupational settings, but mass might not be the appropriate metric as animal studies have shown that nanoparticles (ultrafine particles) produce a stronger adverse effect than fine particles when delivered on an equal mass basis., Methods: This study investigated whether the surface area is a better descriptor than mass of LSLTP of their ability to stimulate pro-inflammatory responses in vitro. In a human alveolar epithelial type II-like cell line, A549, we measured interleukin (IL)-8 mRNA, IL8 protein release and glutathione (GSH) depletion as markers of pro-inflammatory effects and oxidative stress after treatment with a range of LSLTP (fine and nanoparticles) and DQ12 quartz, a particle with a highly reactive surface., Results: In all the assays, nanoparticle preparations of titanium dioxide (TiO2-np) and of carbon black (CB-np) produced much stronger pro-inflammatory responses than the same mass dose of fine TiO2 and CB. The results of the GSH assay confirmed that oxidative stress was involved in the response to all the particles, and two ultra-fine metal dusts (cobalt and nickel) produced GSH depletion similar to TiO2-np, for similar surface-area dose. As expected, DQ12 quartz was more inflammatory than the low toxicity dusts, on both a mass and surface-area basis., Conclusion: Dose-response relationships observed in the in vitro assays appeared to be directly comparable with dose-response relationships in vivo when the doses were similarly standardised. Both sets of data suggested a threshold in dose measured as surface area of particles relative to the surface area of the exposed cells, at around 1-10 cm2/cm2. These findings are consistent with the hypothesis that surface area is a more appropriate dose metric than mass for the pro-inflammatory effects of LSLTP in vitro and in vivo, and consequently that the high surface area of nanoparticles is a key factor in their inflammogenicity.

Introduction: Orthodontically induced inflammatory root resorption is a common complication in orthodontic treatment. Fluoride has been reported to have a beneficial effect against root resorption in dental traumatology. The effect of fluoride on orthodontically induced inflammatory root resorption has not been investigated. This study was undertaken to investigate the effect of fluoride on the incidence of root resorption., Methods: Thirty-two female 8-week-old Wistar rats were separated into 4 groups. Two groups (6 rats per group) were controls; they did not undergo orthodontic tooth movement. The other 2 groups (10 rats per group) had orthodontic tooth movement consisting of activated 100-g closing nickel-titanium coils (NiTi 10-000-06, GAC International, Bohemia, NY) connecting the mandibular first molar to the incisors. Fluoridated water (100 ppm) was given ad libitum to 1 control and 1 experimental group. The other 2 groups received deionized water. After 2 weeks, the animals were killed, and the samples were harvested. Resorption craters were scanned with a Micro CT (SkyScan 1072, Aartselaar, Belgium). Software analysis of the scanned samples provided a volumetric measurement of the resorption craters on the mandibular molar cementum surface., Results: Resorption sites were found in the control samples, especially on the distal surfaces; this could be attributed to normal physiological tooth drift. Resorption sites were significantly (P <.05) increased in the groups receiving orthodontic tooth movement., Conclusions: Fluoride reduces the size of resorption craters, but the effect is variable and not statistically significant (P >.05).

Current techniques for reinnervation of the larynx following recurrent laryngeal nerve (RLN) injury are limited by synkinesis, which prevents functional recovery. Treatment with neurotrophins (NT) may enhance nerve regeneration and encourage more accurate reinnervation. This study presents the results of using the phrenic nerve transfer method, combined with NT-3 treatment, to selectively reinnervate the posterior cricoarytenoid (PCA) abductor muscle in a pig nerve injury model. RLN transection altered the phenotype and morphology of laryngeal muscles. In both the PCA and thyroarytenoid (TA) adductor muscle, fast type myosin heavy chain (MyHC) protein was decreased while slow type MyHC was increased. These changes were accompanied with a significant reduction in muscle fibre diameter. Following nerve repair there was a progressive normalization of MyHC phenotype and increased muscle fibre diameter in the PCA but not the TA muscle. This correlated with enhanced abductor function indicating the phrenic nerve accurately reinnervated the PCA muscle. Treatment with NT-3 significantly enhanced phrenic nerve regeneration but led to only a small increase in the number of reinnervated PCA muscle fibres and minimal effect on abductor muscle phenotype and morphology. Therefore, work exploring other growth factors, either alone or in combination with NT-3, is required.