Assessment of high-dose acetylcysteine in acute high-risk paracetamol (acetaminophen) ingestion.

BACKGROUND: Prompt acetylcysteine treatment with standard doses (300 mg/kg over 21 h in divided doses) is almost universally effective in preventing hepatotoxicity after paracetamol (acetaminophen) overdose. However, hepatotoxicity is reported despite early treatment when paracetamol concentrations exceed 300 mg/L (1,985 µmol/L) at 4 h. Prior studies evaluating high-dose acetylcysteine to treat high-risk ingestions have shown mixed results. We compared outcomes in patients with high-risk ingestions receiving standard or high-dose acetylcysteine. METHODS: Records from a single poison center were reviewed from 1 January 2017 to 31 December 2022. We included cases of acute paracetamol ingestion treated with intravenous acetylcysteine with an initial paracetamol concentration above the "300 mg/L" (1,985 µmol/L) line on the Rumack-Matthew nomogram. We compared standard and high-dose acetylcysteine groups by odds ratios and multivariable logistic regression. We defined hepatotoxicity as aminotransferase activity >1,000 U/L. RESULTS: We included 190 cases. Fifty-six percent received standard-dose acetylcysteine while 44% received high-dose acetylcysteine. Treatment within 8 h yielded no difference in hepatotoxicity between groups (odds ratio 1.67, 95% CI 0.067-42.3). Among patients treated after 8 h, hepatoxicity was more common in the high-dose group (odds ratio 3.39, 95% CI 1.25-9.2) though odds of liver failure were similar (odds ratio 2.78, 95% CI 0.89-8.69). Eighty-eight percent of patients with hepatotoxicity had elevated aminotransferase activity at presentation. No patient died or received a liver transplant. DISCUSSION: Rates of hepatotoxicity were low in patients treated within 8 h regardless of acetylcysteine dose. Unexpectedly, high-dose acetylcysteine treatment was associated with an increased odds of hepatoxicity in those treated after 8 h, but most had abnormal aminotransferase activities at presentation and there was no difference in rates of liver failure. Limitations include the use of retrospective, voluntarily reported poison center data. CONCLUSIONS: Prompt treatment with acetylcysteine, regardless of dose, prevented hepatotoxicity in high-risk paracetamol ingestion.

Acute leukemia with KMT2A rearrangement: A master of disguise.

Mixed-phenotype acute leukemia (MPAL) is a rare form of leukemia with ambiguous lineage, and there are challenges in accurately diagnosing this entity according to formal criteria. Here we report a case which was initially diagnosed as "AML" based on atypical peripheral blood flow cytometry that was subsequently determined to be B-ALL with KMT2A rearrangement based on marrow results. Although KMT2A rearrangements represent a defining genetic abnormality for acute leukemia of ambiguous lineage, this case did not meet the criteria for MPAL based on WHO 2022 criteria. This case highlights the diagnostic challenges of MPAL and the potential limitations of the current classification. We discuss the most appropriate workup and management of these patients and identify areas for future study.

Corrigendum: Comparative microbiome analysis of beef cattle, the feedyard environment, and airborne particulate matter as a function of probiotic and antibiotic use, and change in pen environment.

[This corrects the article DOI: 10.3389/fmicb.2024.1348171.].

Parenting Measures and Their Psychometrics in LGBTQIA+ Families: A Systematic Review.

Parenting significantly influences youth development, yet there's a dearth of research on measuring parenting among LGBTQIA+ caregivers, or caregivers of LGBTQIA+ children (hereafter LGBTQIA+ families). In this systematic review we identified and evaluated the psychometrics of parenting scales validated for this population. The inclusion criteria encompassed studies with LGBTQIA+ families in major databases and secondary sources, psychometric assessment, and English language. Eight studies validating ten scales measuring parenting practices, parental attitudes, beliefs, and perceptions were identified. Generally, studies reported promising psychometrics, showing evidence of construct validity in all and reliability in seven. However, the review also unveiled crucial gaps: a paucity of scales validated among LGBTQIA+ fathers, and predominantly featured non-Hispanic White participants. Findings underscore the necessity for more inclusive samples that reflect the diversity of LGBTQIA+ families. The validation of parenting scales is crucial for understanding parenting in LGBTQIA+ families and developing parenting interventions to promote their well-being.

Comparative microbiome analysis of beef cattle, the feedyard environment, and airborne particulate matter as a function of probiotic and antibiotic use, and change in pen environment.

Introduction: Intensive beef cattle production systems are frequently implicated as a source of bacteria that can be transferred to nearby humans and animals via effluent water, manure used as fertilizer, or airborne particulate matter. It is crucial to understand microbial population dynamics due to manure pack desiccation, antibiotic usage, and antibiotic alternatives within beef cattle and their associated feedyard environment. Understanding how bacterial communities change in the presence of antibiotics can also improve management practices for reducing the spread of foodborne bacteria. Methods: In this study, we aimed to compare the microbiomes within cattle feces, the feedyard environment and artificially produced airborne particulate matter as a function of pen change and treatment with tylosin or probiotics. We utilized 16S rRNA sequencing to compare bacterial communities among sample types, study days, and treatment groups. Results: Bacterial community diversity varied as a function of sampling day and pen change (old or new) within fecal and manure pack samples. Manure pack samples from old pens and new pens contained diverse communities of bacteria on days 0 and 84; however, by day 119 of the study these taxonomic differences were less evident. Particulate matter samples exhibited significant differences in community diversity and predominant bacterial taxa compared to the manure pack they originated from. Treatment with tylosin did not meaningfully impact bacterial communities among fecal, environmental, or particulate matter samples; however, minor differences in bacterial community structure were observed in feces from cattle treated with probiotics. Discussion: This study was the first to characterize and compare microbial communities within feces, manure pack, and airborne particulate matter from the same location and as a function of tylosin and probiotic treatment, and pen change. Although fecal and environmental samples are commonly used in research studies and other monitoring programs to infer public health risk of bacteria and antimicrobial resistance determinants from feedyard environments, our study suggests that these samples may not be appropriate to infer public health risk associated with airborne particulate matter.

AAPM Medical Physics Practice Guideline 8.b: Linear accelerator performance tests.

The purpose of this guideline is to provide a list of critical performance tests to assist the Qualified Medical Physicist (QMP) in establishing and maintaining a safe and effective quality assurance (QA) program. The performance tests on a linear accelerator (linac) should be selected to fit the clinical patterns of use of the accelerator and care should be given to perform tests which are relevant to detecting errors related to the specific use of the accelerator. Current recommendations for linac QA were reviewed to determine any changes required to those tests highlighted by the original report as well as considering new components of the treatment process that have become common since its publication. Recommendations are made on the acquisition of reference data, routine establishment of machine isocenter, basing performance tests on clinical use of the linac, working with vendors to establish QA tests and performing tests after maintenance and upgrades. The recommended tests proposed in this guideline were chosen based on consensus of the guideline's committee after assessing necessary changes from the previous report. The tests are grouped together by class of test (e.g., dosimetry, mechanical, etc.) and clinical parameter tested. Implementation notes are included for each test so that the QMP can understand the overall goal of each test. This guideline will assist the QMP in developing a comprehensive QA program for linacs in the external beam radiation therapy setting. The committee sought to prioritize tests by their implication on quality and patient safety. The QMP is ultimately responsible for implementing appropriate tests. In the spirit of the report from American Association of Physicists in Medicine Task Group 100, individual institutions are encouraged to analyze the risks involved in their own clinical practice and determine which performance tests are relevant in their own radiotherapy clinics.

Common Arterial Trunk Coexisting With Double-Barreled Aorta.

This case describes the first example of a double-barreled aorta in the setting of a common arterial trunk. Our use of annotated and segmented 3-dimensional models greatly enhanced our ability to elucidate the complex anatomy. (Level of Difficulty: Advanced.).

Structural properties of optically clear bacterial cellulose produced by Komagataeibacter hansenii using arabitol.

Bacterial cellulose (BC) exhibits beneficial properties for use in biomedical applications but is limited by its lack of tunable transparency capabilities. To overcome this deficiency, a novel method to synthesize transparent BC materials using an alternative carbon source, namely arabitol, was developed. Characterization of the BC pellicles was performed for yield, transparency, surface morphology, and molecular assembly. Transparent BC was produced using mixtures of glucose and arabitol. Zero percent arabitol pellicles exhibited 25% light transmittance, which increased with increasing arabitol concentration through to 75% light transmittance. While transparency increased, overall BC yield was maintained indicating that the altered transparency may be induced on a micro-scale rather than a macro-scale. Significant differences in fiber diameter and the presence of aromatic signatures were observed. Overall, this research outlines methods for producing BC with tunable optical transparency, while also bringing new insight to insoluble components of exopolymers produced by Komagataeibacter hansenii.

Nivolumab-Induced Myasthenia Gravis Concomitant With Myocarditis, Myositis, and Hepatitis.

We report a case of myasthenia gravis, myocarditis, and myositis following the treatment of melanoma with nivolumab. The patient was a 68-year-old Caucasian male with stage 3 melanoma status after two doses of nivolumab with shortness of breath, intermittent palpitations, dizziness, and nausea. During his initial evaluation, he was found to have atrial fibrillation with rapid ventricular response along with new-onset proximal muscle weakness, double vision, dysphagia, and ptosis of the right eye. Further diagnostic workup of the pleural effusion with CT of the chest showed large right pleural effusion with adjacent atelectasis. Thoracentesis was completed without complications and resulted in an exudative effusion with negative cytology and cultures. Serologic studies showed elevated troponin and serum creatine kinase, negative acetylcholine receptor antibody, and negative modulating antibody. Despite negative antibody tests, the patient's symptoms suggested a clinical diagnosis of myasthenia gravis. The ice pack test was performed, which showed temporary improvement of the patient's ptosis. Given the suspicion for myasthenia gravis and positive ice pack test, he was treated with corticosteroids, intravenous immunoglobulin (IVIG), and pyridostigmine. He completed a total of three doses of IVIG with improvement in diplopia. Despite steroids and respiratory support with BiPAP (bilevel positive airway pressure), on the 14th day of hospitalization, the patient had multiple organ failure along with worsening respiratory failure. The patient discussed the situation with his family, and they decided on hospice care. The patient was discharged to hospice on admission day 14.

Effect of feeding method on nutrient utilization and cow performance in limit-fed cow-calf systems.

Delivery of limit-fed, complete rations requires significant capital investment, and creates logistical challenges for producers. Deconstruction and separate delivery of roughage and concentrate portions of diets may decrease feeding cost. Two experiments were conducted to evaluate the potential of separately limit-feeding roughage and concentrate. In Experiment 1, 4 ruminally cannulated steers (371 ± 12 kg bodyweight) were used in a 4 × 4 Latin square to evaluate the effects of time of concentrate delivery in deconstructed diets. Intake was restricted to 80% of predicted NEm requirements of a diet consisting of wheat straw (35%), cracked corn (29%), and distillers' grains (27%) formulated to contain 1.58 Mcal NEm/kg. Treatments were: concentrate fed 2 h prior to wheat straw (-2S), concentrate and wheat straw fed as total mixed ration (TMR), concentrate fed 2 h after wheat straw (+2S), and concentrate fed 12 h after wheat straw (+12S). In Experiment 2, 95 mid- to late-gestation cows (503 ± 151 kg) were used in a 112-d trial to evaluate feeding system on cow performance. Cows were assigned to 1 of 12 pens. Treatments were limit-fed the complete diet from Experiment 1 (TMR), fed roughage and concentrate portions of the deconstructed TMR 12 h apart (SEP), and ad libitum bermudagrass hay (HAY). Bodyweight (BW), BCS, and back fat measures were collected every 28 d. In Experiment 1, treatment did not affect DM or OM digestion (P ≥ 0.88), rate of particulate passage (P ≥ 0.55), or ruminal DM fill (P ≥ 0.19). Fill averaged 3.8 kg DM. Nadir of ruminal pH occurred 4-8 h after concentrate was delivered, but mean ruminal pH was not different among treatments (P = 0.22) ranging from 6.4 to 6.6 for +2S and 12S, respectively. In Experiment 2, treatment did not affect final BW (518 kg; P = 0.72) or final BCS (5.6; P = 0.67), but limit-fed strategies tended (P = 0.06) to have greater final RE (137.1, 98.9, and -14.6 Mcal for TMR, SEP, and HAY, respectively). Delivering forage and concentrate separately did not change digestion, and timing of concentrate delivery had only minor effects on ruminal fermentation. Limit-feeding a TMR or separate delivery of roughage and concentrate sustained cow performance compared to ad libitum hay consumption.

Maternal nutrient restriction alters endocrine pancreas development in fetal heifers.

Maternal nutrient restriction during pregnancy alters fetal programming, which modifies the growth and health of the offspring in postnatal life. In cattle, nutrient restriction during pregnancy can be a result of environmental or economic factors, but little is known about how it alters the physiology of the fetus and affects future reproductive or growth efficiency. This study used female monozygotic twins, produced through in vitro fertilization and embryo splitting, to determine the effect of moderate maternal nutrient restriction on fetal development. Recipient Angus cross heifers pregnant with one twin were fed a diet meeting 100% National Research Council (NRC) total energy requirements (n = 4; control), whereas recipient heifers pregnant with the second twin were fed at 70% of NRC total energy requirements (n = 4; restricted) from gestational day (GD) 158 to GD 265 in Calan gate feeders. Recipient heifers were killed at GD 265. Change in maternal metabolic body weight was greater from zero in restricted heifers than controls (P < 0.05); restricted heifers lost weight during the nutrient restriction period. There was no difference in last rib back fat or rib eye area between groups (P > 0.10). There was no difference in fetal weight, uterine weight, or total placentome weight between groups (P > 0.10). The pancreas weight was reduced in restricted fetuses compared with control fetuses (P < 0.01), but there were no other differences in fetal organ weights (P > 0.10). Plasma insulin concentrations were reduced in restricted fetuses compared with controls (P < 0.01), but there was no effect of maternal diet on plasma glucose or glucagon concentrations in the fetus (P > 0.10). Histological analyses of the fetal pancreas revealed no differences in endocrine cell number or localization. Results indicate that a modest late gestation nutritional restriction impairs development of the fetal pancreas in the cow. Additional research will be needed to determine if these developmental changes lead to altered glucose and insulin homeostasis in the adult.

Shedding and characterization of gastrointestinal nematodes of growing beef heifers in Central Texas.

Gastrointestinal nematodes (GIN) do not detrimentally affect cattle to the extent of small ruminants. However, they are developing resistance to drugs used to treat them. Genetic strategies to control the nematodes and/or their detrimental effects could be a sustainable alternative to treatment with drugs. An essential first step in development of such a strategy is characterization of nematode populations in commonly used breed types of cattle in local conditions. Fecal egg counts (FEC) were obtained every two months on a cohort of 53 crossbred Nellore-Angus heifers grazing Central Texas pastures from an average heifer age of 3 months to approximately 2 years of age. For 10 of those 12 sets of samples, coprocultures were set up to characterize gastrointestinal nematode species present. Heifers were ½ Nellore ½ Angus (n = 18) or ¾ Angus » Nellore (n = 35). They were born in the spring of 2014 to cows that were from 3-5 years old. They were maintained as a group throughout weaning, postweaning, exposure to bulls as yearlings, and as pregnant cows through the birth of their first calves. An interaction of breed group with sampling time (P < 0.0001) highlighted favorable FEC of » Nellore heifers as compared to ½ Nellore in all but two sampling times. Fecal egg count means were, in general, higher for heifers of both groups in sampling times up to one year of age. Season effects on FEC may be important, but the effect of age may have obscured their detection. There were few significant correlation coefficients for FEC traits with a variety of production traits of these females. Average FEC residuals were positively correlated (r = 0.28 and 0.41; P < 0.05) with winter coat shedding score evaluated at approximately 17 and 24 months of age. Residual correlations of average FEC with calf weaning weight and incidence of shedding with calf age at weaning (r> 0.3) may be indicative of the increased susceptibility of females that lactate heavily or longer to internal parasite infection. Proportions of GIN genera by sampling day differed from χ 2 expectation (P < 0.0001). Cooperia and Haemonchus species were detected in large proportions in sampling dates that corresponded to heifers less than one year of age. Ostertagia and Trichostrongylus species predominated in sampling dates after heifers reached one year of age.

Shedding and characterization of gastrointestinal nematodes of growing beef heifers in Central Texas.

Gastrointestinal nematodes (GIN) do not detrimentally affect cattle to the extent of small ruminants. However, they are developing resistance to drugs used to treat them. Genetic strategies to control the nematodes and/or their detrimental effects could be a sustainable alternative to treatment with drugs. An essential first step in development of such a strategy is characterization of nematode populations in commonly used breed types of cattle in local conditions. Fecal egg counts (FEC) were obtained every two months on a cohort of 53 crossbred Nellore-Angus heifers grazing Central Texas pastures from an average heifer age of 3 months to approximately 2 years of age. For 10 of those 12 sets of samples, coprocultures were set up to characterize gastrointestinal nematode species present. Heifers were ½ Nellore ½ Angus (n = 18) or ¾ Angus » Nellore (n = 35). They were born in the spring of 2014 to cows that were from 3-5 years old. They were maintained as a group throughout weaning, postweaning, exposure to bulls as yearlings, and as pregnant cows through the birth of their first calves. An interaction of breed group with sampling time (P < 0.0001) highlighted favorable FEC of » Nellore heifers as compared to ½ Nellore in all but two sampling times. Fecal egg count means were, in general, higher for heifers of both groups in sampling times up to one year of age. Season effects on FEC may be important, but the effect of age may have obscured their detection. There were few significant correlation coefficients for FEC traits with a variety of production traits of these females. Average FEC residuals were positively correlated (r = 0.28 and 0.41; P < 0.05) with winter coat shedding score evaluated at approximately 17 and 24 months of age. Residual correlations of average FEC with calf weaning weight and incidence of shedding with calf age at weaning (r> 0.3) may be indicative of the increased susceptibility of females that lactate heavily or longer to internal parasite infection. Proportions of GIN genera by sampling day differed from χ2 expectation (P < 0.0001). Cooperia and Haemonchus species were detected in large proportions in sampling dates that corresponded to heifers less than one year of age. Ostertagia and Trichostrongylus species predominated in sampling dates after heifers reached one year of age.

Macrolide-susceptible probiotic Enterococcus faecium ST296 exhibits faecal-environmental-oral microbial community cycling among beef cattle in feedlots.

Enterococci are included in the United States National Antimicrobial Resistance Monitoring System to track antibiotic resistance among commensal Gram-positive enteric bacteria, largely due to their high abundance in food animals and in retail meat. In the U.S. cattle industry, macrolides are used to prevent and control liver abscesses, which cause significant economic losses. Previous studies have suggested that feeding tylosin and the intensity of the pen environment, both expand and sustain respectively the prevalence of multidrug resistance among enterococci in feedlot cattle. This has led to research into alternative feed supplements and improved stewardship practices. In a randomized controlled trial, we measured the impact of a probiotic and an altered pen environment on antimicrobial resistance among faecal Enterococcus spp. in cattle fed tylosin. Supplementing cattle with an Enterococcus faecium and Saccharomyces cerevisiae-based probiotic yielded the isolation of E. faecium of the probiotic sequence type (ST296) from faecal and environmental samples in treatment groups, as well as from cattle and the manure pack in nearby pens. Of importance, the probiotic strain also was found in a desiccated and milled manure pack sample taken 120 days after the initial trial ended. Phylogenetic and SNP analyses revealed clonal survival and spread compatible with faecal-environmental-oral recycling of the probiotic strain within and among cattle and pens. The increase in prevalence of the ST296 strain occurred concomitant with a decrease in ST240, the dominant sequence type associated with ermB and tet(M) resistance genes in this trial. SIGNIFICANCE AND IMPACT OF THE STUDY: We demonstrate that a macrolide-susceptible probiotic Enterococcus faecium ST296 strain fed to beef cattle becomes fully embedded in the microbial community cycling of bacteria via faecal-environmental-oral transmission within and among feedlot pens. An initial investment in feeding the probiotic is thereby leveraged into expanding numbers of susceptible bacteria in cattle and their environment, even among those cattle fed tylosin.

Predictors of Post-operative Pain and Opioid Consumption in Patients Undergoing Liver Surgery.

BACKGROUND: Post-operative pain management is a critical component of perioperative care. Patients at risk of poorly controlled post-operative pain may benefit from early measures to optimize pain management. We sought to identify risk factors for post-operative pain and opioid consumption in patients undergoing liver resection. METHODS: This is a multi-institutional prospective nested cohort study of patients undergoing open liver resection. Opioid consumption and pain scores were collected following surgery. To estimate the effects of patient factors on opioid consumption (oral morphine equivalents-OME) and on pain scores (NRS-11), we used generalized linear models and multivariable linear regression model, respectively. RESULTS: One hundred and fifty-three patients who underwent open liver resection between 2013 and 2016 were included in the study. The mean patient age was 62.2 years, and 43.3% were female. Younger patients were significantly more likely to use more opioids in the early post-operative period (16.7 OME/10 years, p < 0.001). Patient factors that were significantly associated with increased NRS-11 pain scores also included younger patient age (difference in pain score of 0.3/10 years with cough and 0.2/10 years at rest, p < 0.01 for both) as well as a history of analgesic use (difference in pain score of 0.9 with cough and 0.6 at rest, p < 0.01 and p = 0.07, respectively). CONCLUSION: Younger patients and those with a history of analgesic use are more likely to report higher post-operative pain and require higher doses of opioids. Early identification of these patients, and measures to better manage their pain, may contribute to optimal perioperative care.

Dual laser holography for in situ measurement of plasma facing component erosion (invited).

A digital holography (DH) surface erosion/deposition diagnostic is being developed for 3D imaging of plasma facing component surfaces in situ and in real time. Digital holography is a technique that utilizes lasers reflected from a material surface to form an interferogram, which carries information about the topology of the surface when reconstructed. As described in this paper, dual CO2 lasers at 9.271 and 9.250 µm wavelengths illuminate the interrogated surface (at a distance of ∼1 m) in a region of ∼1 cm × 1 cm. The surface feature resolution is ∼0.1 mm in the plane of the surface, and the depth resolution ranges from ∼0.0001 to ∼2 mm perpendicular to the surface. The depth resolution lower limit is set by single-laser and detector optical limitations, while the upper limit is determined by 2π phase ambiguity of the dual-laser synthetic wavelength. Measurements have been made "on the bench" to characterize the single-laser and dual-laser DH configurations utilizing standard resolution targets and material targets that were previously exposed to high flux plasmas in either the Prototype Material Plasma Exposure eXperiment (Proto-MPEX) or the electro-thermal (ET) arc source. Typical DH measurements were made with 0.03 ms integration with an IR camera that can be framed at rates approaching 1.5 kHz. The DH diagnostic system is progressing toward in situ measurements of plasma erosion/deposition either on Proto-MPEX or the ET arc source.

Comparison of Salmonella Prevalence Rates in Bovine Lymph Nodes across Feeding Stages.

Peripheral lymph nodes (LNs) located in the fatty tissues of beef carcasses have been shown to harbor Salmonella and, thus, potentially contaminate ground beef. Salmonella prevalence within LNs is known to differ among feedlots. Two South Texas feeding operations (identified as locations A and B) known to harbor salmonellae in the feedlot environment, while historically producing cattle with opposing rates (one "high" and one "low") of Salmonella prevalence in LNs, were used in this study. To determine whether this difference was due to cattle source or factors associated with different stages of feeding, weanling steers of common and known origin were followed through normal feeding stages at both operations. Eighty Angus-sired beef steers were harvested at each of four feeding stages: 1, postweaning; 2, background or stocker; 3, 60 days on feed; and 4, 120 days on feed. Left and right subiliac and superficial cervical LNs ( n = 304) were collected from each carcass, and similar node types were pooled by animal ( n = 152). Results showed a difference ( P < 0.05) in prevalence of Salmonella in bovine lymph nodes between location A and location B and among feeding stages in location B. Salmonella was not isolated from any feeding stage 1 (postweaning) or location A LN samples. Within location B, there was an increase in Salmonella prevalence as cattle moved into later stages of feeding: at 22.2% (4 of 18), 77.8% (14 of 18), and 94.4% (17 of 18) for feeding stages 2, 3, and 4, respectively. Although the reasons for the differences seen between feeding operations and for increased Salmonella prevalence in LNs at later feeding stages remain unexplained, these results indicate that factors other than cattle source are likely influencing Salmonella prevalence in LNs.

Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-ß receptor type I inhibitor.

Transforming growth factor-ß (TGFß) is an important driver of tumor growth via intrinsic and extrinsic mechanisms, and is therefore an attractive target for developing cancer therapeutics. Using preclinical models, we characterized the anti-tumor activity of a small molecule inhibitor of TGFß receptor I (TGFßRI), galunisertib (LY2157299 monohydrate). Galunisertib demonstrated potent and selective inhibition of TGFßRI with corresponding inhibition of downstream signaling via inhibition of SMAD phosphorylation (pSMAD). Galunisertib also inhibited TGFß-induced pSMAD in vivo, which enabled a pharmacokinetic/pharmacodynamic profile in Calu6 and EMT6-LM2 tumors. Galunisertib demonstrated anti-tumor activity including inhibition of tumor cell migration and mesenchymal phenotype, reversal of TGFß-mediated immune-suppression, and tumor growth delay. A concentration-effect relationship was established with a dosing schedule to achieve the optimal level of target modulation. Finally, a rat model demonstrated a correlation between galunisertib-dependent inhibition of pSMAD in tumor tissues and in PBMCs, supporting the use of PBMCs for assessing pharmacodynamic effects. Galunisertib has been tested in several clinical studies with evidence of anti-tumor activity observed in subsets of patients. Here, we demonstrate that galunisertib inhibits a number of TGFß-dependent functions leading to anti-tumor activity. The enhanced understanding of galunisertib provides rationale for further informed clinical development of TGFß pathway inhibitors.

Glucose and acetate metabolism in bovine intramuscular and subcutaneous adipose tissues from steers infused with glucose, propionate, or acetate.

We hypothesized that abomasal infusion of glucose would promote de novo fatty acid biosynthesis from glucose in vitro in bovine intramuscular (i.m.) and subcutaneous (s.c.) adipose tissues to a greater extent than ruminal infusion of acetate, propionate, or glucose. Angus crossbred steers (n = 24), 22 mo of age, were fitted with ruminal cannulas, and steers were adapted to another corn/sorghum finishing diet over a 2-wk period while recovering from the placement of the cannulas. After the adaptation period, the steers were fed the second finishing diet at 130% of their voluntary intake and were infused with isocaloric amounts (3.76 Mcal/d) of glucose, propionate, or acetate for 35 d. Glucose was infused either into the rumen or into the abomasum, whereas propionate and acetate were infused into the rumen. Acetate infusion decreased DM and DE intakes (P < 0.05). The 5th to 8th longissimus muscle section was removed immediately and transported to the laboratory within 10 min post-exsanguination in 38 °C, oxygenated Krebs Henseleit buffer containing 5 mM glucose and 5 mM acetate. Intramuscular and s.c. adipose tissues were dissected from the muscle and incubated in vitro in 5 mM glucose plus 5 mM acetate (containing [U-14C]glucose or [1-14C]acetate). Lipid content was lower (P = 0.04) in i.m. adipose tissue of the acetate-infused steers than in the other treatment groups, and i.m. adipocytes from acetate-infused steers were smaller (P = 0.01) than those from propionate-infused steers. The rate of incorporation of acetate into glyceride-fatty acids (GFA) in i.m. and s.c. adipose tissues was greater (P < 0.03) in steers receiving ruminal or abomasal infusions of glucose than in adipose tissues from steers infused with acetate. The greatest rates of GFA synthesis were observed in s.c. adipose tissue from steers infused ruminally with propionate or abomasally infused with glucose (P < 0.001). In i.m. and s.c. adipose tissues, the proportion of acetyl units from acetate incorporated into GFA was greater in steers receiving glucose infusion in the rumen or abomasum than in steers receiving acetate or propionate infusion (P < 0.05). Contrary to our hypothesis, abomasal glucose infusion did not promote greater fatty acid biosynthesis from glucose in i.m. adipose tissue than ruminal glucose infusion. However, glucose infusion caused the greatest production of acetyl units from acetate in i.m. and s.c. adipose tissues.

Clinically apparent adverse reactions to intra-wound vancomycin powder in early onset scoliosis are rare.

PURPOSE: Spine surgeons have increasingly used intraoperative application of topical vancomycin powder (TVP) to prevent surgical site infections (SSIs). The goals of this study were to define the rate of pharmacological adverse reaction to TVP in young patients undergoing posterior spinal surgery and to summarise institutional variation in TVP dosing. METHODS: This retrospective observational study included ten spine centres in the United States and one in Europe. Patients with early onset scoliosis who underwent posterior spine surgery were eligible for inclusion. Age, weight, TVP dose and surgery type were recorded. Surgeries where patient age was > 12 years were excluded. Pharmacological adverse reactions were defined as clinical instances of Red Man Syndrome, rash, nephrotoxicity, proteinuria, hepatotoxicity or ototoxicity. The rate of pharmacological adverse reaction to TVP was calculated. Dosing practices were summarised. RESULTS: Patient age was in the range of seven months to 12 years (median ten years). Of 1398 observations, there was one possible pharmacological adverse reaction. This was in a ten-year-old, 20.4-kg female patient with neuromuscular sco-liosis undergoing growing rod implantation. She was dosed with 1500 mg of TVP and immediately developed a transient rash without systemic symptoms. This abated over minutes without any medical intervention. There were no other adverse reactions in the sample. The population rate of pharmacological adverse reaction was 0.072% (95% confidence interval 0 to 0.4). Significant variability in dosing practices existed between centres. CONCLUSION: Pharmacological adverse reactions to TVP are rare. Future work may establish evidence-based guidelines for TVP dosing based on patient weight and other variables.