Influence of low-level tannin supplementation on comparative growth performance of Holstein and Angus × Holstein cross calf-fed concentrate-based finishing diets for 328 d.

The objective of the current study was to evaluate the effects of tannin and monensin supplementation in feedlot diets and breed (Holstein vs. Angus × Holstein) on growth performance, energetic efficiency, and carcass characteristics. Eighty purebred Holstein calves (HOL; initial body weight (BW) = 130 ±â€…5 kg) and 80 Angus × Holstein calves (AXH; initial BW = 129 ±â€…6 kg) were blocked by initial BW and randomly assigned to 40 pens. Dietary treatments consisted of a steam-flaked corn-based diet supplemented with (1) no feed additive (CON); (2) 30 mg of monensin/kg of dry matter (DM; MON; Rumensin 90, Elanco, Greenfield, IN); (3) 1.5 g tannin)/kg of DM (TAN; ByPro, 70% condensed tannin, SilvaFeed, Indunor, S.A., Buenos Aires, Argentina); (4) M + T, the combination of MON plus TAN dietary treatments. Data were analyzed as a randomized complete block in a 2 × 4 factorial arrangement of treatments, using pens as experimental units. There were no interactions (P > 0.05) between feed additives and breed. Supplemental MON increased (P ≤ 0.04) initial 112-d BW and gain efficiency. However, there were no dietary treatment effects (P > 0.10) on overall growth performance. Monensin supplementation decreased (P = 0.04) minimum daily ruminal temperature compared with other dietary treatments during July, but TAN did not affect ruminal temperature. Holstein steers had greater (P = 0.04) overall DM intake compared with AXH, with no difference (P = 0.19) in overall ADG, leading to increased (P < 0.01) gain efficiency for AXH compared with HOL. Dietary net energy for maintenance and gain, based on growth performance, were greater (P ≤ 0.01) for AXH vs HOL. Compared with HOL, AXH steers had greater (P ≤ 0.01) carcass weight, dressing percentage, kidney, pelvic, and heart fat, 12th rib fat thickness, longissimus area, and preliminary yield grade. Holstein steers had lower (P ≤ 0.04) minimum average ruminal temperature during June compared with AXH, with no differences (P ≥ 0.14) between breeds during July or August. Results indicate that feed additives did not appreciably affect steer growth performance and carcass characteristics, but crossbred AXH steers had greater growth performance, efficiency of dietary energy utilization, and carcass quality measures compared with HOL. This study observed a reduction (4.7%) in maintenance energy expenditure in AXH compared with HOL, implying in maintenance energy coefficient of 0.086 vs 0.082 for HOL and AXH, respectively.

Effects of tannin and monensin supplementation on growth performance, energetic efficiency, and carcass characteristics were evaluated in Holstein and Angus × Holstein steers. The investigation used a factorial design to access the impacts of both feed additives and breed on the study's parameters. Tannin supplementation did not affect growth performance. There were no dietary treatment effects on overall steer growth performance. Calf Holstein steers were fed with grain diet based. Holstein steers had greater overall DM intake than Angus × Holstein steers, but breed did not affect average daily gain. Thus, gain efficiency was greater for Angus × Holstein vs Holstein steers. There was no effect of dietary treatment on carcass measures. Compared with Holsteins, Angus × Holstein steers had greater carcass weight, dressing percentage, internal and external fat, longissimus area, and marbling score than Holstein steers. The current study suggests that monensin and tannin supplementation did not affect overall steer growth performance and carcass characteristics. Compared with Holsteins, crossbred Angus × Holstein steers had increased growth performance and carcass quality measures.

Intake of B vitamins and the risk of developing islet autoimmunity and type 1 diabetes in the TEDDY study.

PURPOSE: The aim was to study the association between dietary intake of B vitamins in childhood and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D) by the age of 10 years. METHODS: We followed 8500 T1D-susceptible children born in the U.S., Finland, Sweden, and Germany in 2004 -2010 from the Environmental Determinants of Diabetes in the Young (TEDDY) study, which is a prospective observational birth cohort. Dietary intake of seven B vitamins was calculated from foods and dietary supplements based on 24-h recall at 3 months and 3-day food records collected regularly from 6 months to 10 years of age. Cox proportional hazard models were adjusted for energy, HLA-genotype, first-degree relative with T1D, sex, and country. RESULTS: A total of 778 (9.2) children developed at least one autoantibody (any IA), and 335 (3.9%) developed multiple autoantibodies. 280 (3.3%) children had IAA and 319 (3.8%) GADA as the first autoantibody. 344 (44%) children with IA progressed to T1D. We observed that higher intake of niacin was associated with a decreased risk of developing multiple autoantibodies (HR 0.95; 95% CI 0.92, 0.98) per 1 mg/1000 kcal in niacin intake. Higher intake of pyridoxine (HR 0.66; 95% CI 0.46, 0.96) and vitamin B12 (HR 0.87; 95% CI 0.77, 0.97) was associated with a decreased risk of IAA-first autoimmunity. Higher intake of riboflavin (HR 1.38; 95% CI 1.05, 1.80) was associated with an increased risk of GADA-first autoimmunity. There were no associations between any of the B vitamins and the outcomes "any IA" and progression from IA to T1D.  CONCLUSION: In this multinational, prospective birth cohort of children with genetic susceptibility to T1D, we observed some direct and inverse associations between different B vitamins and risk of IA.

A century of studying plant secondary metabolism-From "what?" to "where, how, and why?"

Over the past century, early advances in understanding the identity of the chemicals that collectively form a living plant have led scientists to deeper investigations exploring where these molecules localize, how they are made, and why they are synthesized in the first place. Many small molecules are specific to the plant kingdom and have been termed plant secondary metabolites, despite the fact that they can play primary and essential roles in plant structure, development, and response to the environment. The past 100 yr have witnessed elucidation of the structure, function, localization, and biosynthesis of selected plant secondary metabolites. Nevertheless, many mysteries remain about the vast diversity of chemicals produced by plants and their roles in plant biology. From early work characterizing unpurified plant extracts, to modern integration of 'omics technology to discover genes in metabolite biosynthesis and perception, research in plant (bio)chemistry has produced knowledge with substantial benefits for society, including human medicine and agricultural biotechnology. Here, we review the history of this work and offer suggestions for future areas of exploration. We also highlight some of the recently developed technologies that are leading to ongoing research advances.

Brain glutathione and GABA+ levels in autistic children.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered neurometabolite levels, including glutathione (GSH) and gamma-aminobutyric acid (GABA), have been proposed as potential contributors to the biology underlying ASD. This study investigated whether cerebral GSH or GABA levels differ between a cohort of children aged 8-12 years with ASD (n = 52) and typically developing children (TDC, n = 49). A comprehensive analysis of GSH and GABA levels in multiple brain regions, including the primary motor cortex (SM1), thalamus (Thal), medial prefrontal cortex (mPFC), and supplementary motor area (SMA), was conducted using single-voxel HERMES MR spectroscopy at 3T. The results revealed no significant differences in cerebral GSH or GABA levels between the ASD and TDC groups across all examined regions. These findings suggest that the concentrations of GSH (an important antioxidant and neuromodulator) and GABA (a major inhibitory neurotransmitter) do not exhibit marked alterations in children with ASD compared to TDC. A statistically significant positive correlation was observed between GABA levels in the SM1 and Thal regions with ADHD inattention scores. No significant correlation was found between metabolite levels and hyper/impulsive scores of ADHD, measures of core ASD symptoms (ADOS-2, SRS-P) or adaptive behavior (ABAS-2). While both GSH and GABA have been implicated in various neurological disorders, the current study provides valuable insights into the specific context of ASD and highlights the need for further research to explore other neurochemical alterations that may contribute to the pathophysiology of this complex disorder.

Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval.

OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

Neurotransmitter levels in the basal ganglia are associated with intracortical circuit activity of the primary motor cortex in healthy humans.

BACKGROUND: The basal ganglia are strongly connected to the primary motor cortex (M1) and play a crucial role in movement control. Interestingly, several disorders showing abnormal neurotransmitter levels in basal ganglia also present concomitant anomalies in intracortical function within M1. OBJECTIVE/HYPOTHESIS: The main aim of this study was to clarify the relationship between neurotransmitter content in the basal ganglia and intracortical function at M1 in healthy individuals. We hypothesized that neurotransmitter content of the basal ganglia would be significant predictors of M1 intracortical function. METHODS: We combined magnetic resonance spectroscopy (MRS) and transcranial magnetic stimulation (TMS) to test this hypothesis in 20 healthy adults. An extensive TMS battery probing common measures of intracortical, and corticospinal excitability was administered, and GABA and glutamate-glutamine levels were assessed from voxels placed over the basal ganglia and the occipital cortex (control region). RESULTS: Regression models using metabolite concentration as predictor and TMS metrics as outcome measures showed that glutamate level in the basal ganglia significantly predicted short interval intracortical inhibition (SICI) and intracortical facilitation (ICF), while GABA content did not. No model using metabolite measures from the occipital control voxel was significant. CONCLUSIONS: Taken together, these results converge with those obtained in clinical populations and suggest that intracortical circuits in human M1 are associated with the neurotransmitter content of connected but distal subcortical structures crucial for motor function.

Hypnosis and suggestion as interventions for functional neurological disorder: A systematic review.

OBJECTIVE: Functional neurological disorder (FND) involves the presence of neurological symptoms that cannot be explained by neurological disease. FND has long been linked to hypnosis and suggestion, both of which have been used as treatments. Given ongoing interest, this review examined evidence for the efficacy of hypnosis and suggestion as treatment interventions for FND. METHOD: A systematic search of bibliographic databases was conducted to identify group studies published over the last hundred years. No restrictions were placed on study design, language, or clinical setting. Two reviewers independently assessed papers for inclusion, extracted data, and rated study quality. RESULTS: The search identified 35 studies, including 5 randomised controlled trials, 2 non-randomised trials, and 28 pre-post studies. Of 1584 patients receiving either intervention, 1379 (87%) showed significant improvements, including many who demonstrated resolution of their symptoms in the short-term. Given the heterogeneity of interventions and limitations in study quality overall, more formal quantitative synthesis was not possible. CONCLUSIONS: The findings highlight longstanding and ongoing interest in using hypnosis and suggestion as interventions for FND. While the findings appear promising, limitations in the evidence base, reflecting limitations in FND research more broadly, prevent definitive recommendations. Further research seems warranted given these supportive findings.

Leucine Supplementation Exacerbates Morbidity in Male but Not Female Mice with Colorectal Cancer-Induced Cachexia.

Cancer cachexia (CC) is a multifactorial wasting syndrome characterized by a significant loss in lean and/or fat mass and represents a leading cause of mortality in cancer patients. Nutraceutical treatments have been proposed as a potential treatment strategy to mitigate cachexia-induced muscle wasting. However, contradictory findings warrant further investigation. The purpose of this study was to determine the effects of leucine supplementation on skeletal muscle in male and female ApcMin/+ mice (APC). APC mice and their wild-type (WT) littermates were given normal drinking water or 1.5% leucine-supplemented water (n = 4-10/group/sex). We measured the gene expression of regulators of inflammation, protein balance, and myogenesis. Leucine treatment lowered survival rates, body mass, and muscle mass in males, while in females, it had no effect on body or muscle mass. Leucine treatment altered inflammatory gene expression by lowering Il1b 87% in the APC group and decreasing Tnfa 92% in both WT and APC males, while it had no effect in females (p < 0.05). Leucine had no effect on regulators of protein balance and myogenesis in either sex. We demonstrated that leucine exacerbates moribundity in males and is not sufficient for mitigating muscle or fat loss during CC in either sex in the ApcMin/+ mouse.

Suppression of cortical electrostimulation artifacts using pre-whitening and null projection.

Objective.Invasive brain-computer interfaces (BCIs) have shown promise in restoring motor function to those paralyzed by neurological injuries. These systems also have the ability to restore sensation via cortical electrostimulation. Cortical stimulation produces strong artifacts that can obscure neural signals or saturate recording amplifiers. While front-end hardware techniques can alleviate this problem, residual artifacts generally persist and must be suppressed by back-end methods.Approach.We have developed a technique based on pre-whitening and null projection (PWNP) and tested its ability to suppress stimulation artifacts in electroencephalogram (EEG), electrocorticogram (ECoG) and microelectrode array (MEA) signals from five human subjects.Main results.In EEG signals contaminated by narrow-band stimulation artifacts, the PWNP method achieved average artifact suppression between 32 and 34 dB, as measured by an increase in signal-to-interference ratio. In ECoG and MEA signals contaminated by broadband stimulation artifacts, our method suppressed artifacts by 78%-80% and 85%, respectively, as measured by a reduction in interference index. When compared to independent component analysis, which is considered the state-of-the-art technique for artifact suppression, our method achieved superior results, while being significantly easier to implement.Significance.PWNP can potentially act as an efficient method of artifact suppression to enable simultaneous stimulation and recording in bi-directional BCIs to biomimetically restore motor function.

Effect of Combining the Ionophore Monensin with Natural Antimicrobials Supplemented in the Last Phase of Finishing of Lambs: Growth Performance, Dietary Energetics, and Carcass Characteristics.

With the aim of evaluating the effect of combining an antibiotic ionophore with plant extracts and probiotics on the productive efficiency (performance and carcass) during the last phase of lamb fattening, 24 Pelibuey × Katahdin male lambs (38.47 ± 3.92 kg, initial weight) were fed with a high-energy diet during for 56 days, and assigned, under a complete randomized block design experiment to one of the following supplement treatments: (1) 28 mg of monensin/kg diet DM supplemented alone (MON), (2) combination of MON plus 2 g/kg diet of a product contained Bacillus subtilis 2.2 × 108 CFU kg diet DM (MON + BS), (3) combination of MON + BS plus 300 mg essential oils/kg diet DM (MON + BS + EO), and (4) BS alone. At the end of the feeding trial (56-d), lambs were slaughtered and carcass variables were measured. Compared to the rest of the treatments, combining MON with BS improved dietary NE by 3.4% and the efficiency of utilization of dietary energy consumed. Inclusion of EO in the MON + BS combination resulted in a similar average daily weight gain (ADG) and feed efficiency (GF) when compared with MON + BS, but showed a lower dietary net energy (NE), hot carcass weight, and dressing percentage. Lambs receiving BS alone showed greater average ADG and dry matter intake (DMI) than lambs receiving MON + BS + EO, but similar feed GF and dietary NE. There were no treatment effects on tissue composition, whole cut, or visceral organ mass. It was concluded that combining probiotics with the ionophore monensin can improve the efficiency of dietary energy utilization in the last phase of finishing. Probiotics supplemented alone result in greater ADG without a difference in dietary energy efficiency when compared with MON alone. Inclusion of EO in the MON + BS combination did not show advantages; on the contrary, it reduced carcass weight and dressing percentage. It is necessary to further research the potential complementary effects of combining diverse sources of natural additives with synthetic antibiotics.

Essential Oils Combined with Vitamin D3 or with Probiotic as an Alternative to the Ionophore Monensin Supplemented in High-Energy Diets for Lambs Long-Term Finished under Subtropical Climate.

Supplementation with natural additives such as essential oils (EO) or probiotics has resulted in comparable growth performance to that of supplemental monensin in fattening lambs in hot environments. Supra-supplementation levels of vitamin D3 improved the carcass weight and dressing percentage of steers fattened under tropical conditions. We hypothesized that certain combinations of these natural additives could be complementary. For this reason, a feeding trial was carried out using 48 Pelibuey × Katahdin non-castrated male lambs (107 ± 14 d age; 17.9 ± 2.51 kg LW). Lambs were fed an 88:12 concentrate to forage ratio basal diet supplemented (dry matter basis, DMI) with: (1) no additive (CON); (2) 28 mg monensin/kg diet (MON); (3) 150 mg of essential oils containing a combination of thymol, eugenol, vanillin, guaiac, and limonene plus 0.12 mg vitamin D3 (EO + D3)/kg diet; and (4) 300 mg of essential oils containing a combination of carvacrol and cynamaldehyde plus 2 g probiotic (2.2 × 108 CFU of bacillus subtilis/kg diet, EO + BS). Lambs were grouped by initial weight and assigned within six weight groupings to 24 pens (2 lambs/pen, 6 replicas per treatment) in a randomized complete block design. The experiment lasted 121 days. Daily maximal THI exceeded the 80 "danger or "emergency" range for 119 days of the 121 days of the trial. Lambs supplemented with MON had similar DMI, growth performance, and dietary energetics to those of CON lambs. Lambs supplemented with EO + BS had a greater (9.2%, p ≤ 0.05) average daily gain (ADG) than the CON and MON groups due to enhanced (10.2%, p ≤ 0.05) dry matter intake. Thus, gain efficiency (GF) and estimated dietary energy were similar for CON, MON, and EO + BS. Lambs receiving EO + D3 had similar (0.254 vs. 0.262 kg/d) ADG but a lower DMI (8%, p < 0.05) compared with EO + BS lambs. Consequently, GF and estimated dietary net energy were greater (4.9 and 3.7%, respectively; p ≤ 0.05) for EO + D3 lambs. Even when ambient heat load was elevated, the efficiency of utilization of dietary energy (observed-to-expected dietary net energy) was close to 1.00 (0.992) expected for EO + D3 lambs. In contrast, efficiency of energy utilization was depressed by -4.4% for lambs on the other treatments. Compared with the other treatments, lambs receiving EO + D3 had greater longissimus muscle area (5.6%, p < 0.05) and lower kidney pelvic fat (21.8%, p ≤ 0.05). There were no treatment effects on shoulder tissue composition or whole cuts (expressed as % of cold carcass weight). Compared to CON, lambs that were fed with natural additives showed 3.5% lower (p ≤ 0.05) intestine mass. All supplemental additives decreased visceral fat mass, which was minimal with EO + D3 treatment. Combinations of essential oils with vitamins or probiotics were superior to antibiotic monensin in finishing diets for feedlot lambs. Combining EO with probiotics promoted DM intake and gain but not gain efficiency, while combining EO with vitamin D3 supra-supplementation increased dietary energy efficiency and improved some carcass characteristics in lambs fattening under high ambient heat loads.

Implementing structured pathology reporting protocol for non-melanocytic skin cancers: practical considerations.

Non-melanocytic skin cancers (NMSCs) account for five times the incidence of all other cancers combined and cost US $6 billion annually. These are the most frequent specimens encountered in community pathology practice in many Western countries. Lack of standardised structured pathology reporting protocols (SPRPs) can result in omission of critical information or miscommunication leading to suboptimal patient management. The lack of standardised data has significant downstream public health implications, including insufficient data for reliable development of prognostic tools and health-economy planning. The Royal College of Pathologists of Australasia has developed an NMSC SPRP. A multidisciplinary expert committee including pathologists, surgeons, dermatologists, and radiation and medical oncologists from high volume cancer centres was convened. A systematic literature review was performed to identify evidence for including elements as mandatory standards or best practice guidelines. The SPRP and accompanying commentary of evidence, definitions and criteria was peer reviewed by external stakeholders. Finally, the protocol was revised following feedback and trialled in multiple centres prior to implementation. Some parameters utilised clinically for determining management and prognosis including tumour depth, lymphovascular invasion or distance to the margins lack high level evidence in NMSC. Dermatologists, surgeons, and radiation oncologists welcomed the SPRP. Pathologists indicated that the variety of NMSC specimens ranging from curettes to radical resections as well as significant differences in the biological behaviour of different tumours covered by the NMSC umbrella made use of a single protocol difficult. The feedback included that using a SPRP for low risk NMSC was neither clinically justified nor compensated adequately by the Australian Medicare Reimbursement Schedule. Following stakeholder feedback, the SPRP implementation was restricted to excision specimens of head and neck NMSC; and low-risk NMSC, such as superficial basal cell carcinoma, were excluded. Implementing NMSC SPRP fulfils an unmet clinical need. Unlike other cancers, NMSCs generate a range of specimen types and are reported in a wide range of pathology practices. Limiting use of SPRP to NMSC at higher risk of progression and providing formatted templates for easy incorporation into laboratory information systems were essential to successful deployment. In the future, further consideration should be given to implementing the SPRP to include all relevant specimens, including non-head and neck and low-risk NMSC specimens.

A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial of adjunctive N-Acetylcysteine for treatment-resistant PTSD.

BACKGROUND: PTSD may involve oxidative stress, and N-acetylcysteine (NAC) may reduce the impact of oxidative stress in the brain. This study aims to investigate the efficacy of adjuvant NAC in people with treatment-resistant PTSD. METHODS: A multicentre, randomised, double-blind, placebo-controlled trial for adults with PTSD unresponsive to first-line treatment. The intervention was either oral NAC 2.7 g/day or placebo for 12 weeks. The primary outcome was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at 12 weeks compared with baseline. Secondary outcomes included depression and substance craving. Follow-up measures were obtained at 16 and 64-weeks. RESULTS: 133 patients were assessed, with 105 randomised; 81 participants completed the 12-week trial, 79 completed week-16 follow-up, and 21 completed week-64 follow-up. There were no significant differences between those taking NAC and those taking placebo in CAPS-5 scores at week 12, nor in secondary outcomes. Significant between-group differences were observed at week 64 in craving duration (Cohen's d = 1.61) and craving resistance (Cohen's d = 1.03), both in favour of NAC. CONCLUSION: This was the first multicentre, double-blind, randomised, placebo-controlled trial of adjunctive NAC for treatment-resistant PTSD. No benefit of NAC was observed in this group beyond that provided by placebo at end of the trial. TRIAL REGISTRATION: ACTRN12618001784202, retrospectively registered 31/10/2018, URL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376004.

Cisplatin exhibits superiority over MMC as a perfusion agent in a peritoneal mesothelioma patient specific organoid HIPEC platform.

Peritoneal mesothelioma (PM) is a rare malignancy with poor prognosis, representing about 10-15% of all mesothelioma cases. Herein we apply PM patient-derived tumor organoids (PTOs) in elucidating personalized HIPEC responses to bypass rarity of disease in generating preclinical data. Specimens were obtained from PM patients undergoing cytoreductive surgery with HIPEC. PTOs were fabricated with tumor cells suspended in ECM-hydrogel and treated with HIPEC regimen parameters. Viability and characterization analyses were performed post-treatment. Treatment efficacy was defined as ≥ 50% viability reduction and p < 0.05 compared to controls. From October 2020 to November 2022, 17 tumors from 7 patients were biofabricated into organoids, with 16/17 (94.1%) sites undergoing comparative 37° and 42° treatments with cisplatin and mitomycin C (MMC). Hyperthermic cisplatin and MMC enhanced cytotoxicity which reduced treatment viability by 25% and 22%, respectively, compared to normothermia. Heated cisplatin displayed the greatest cytotoxicity, with efficacy in 12/16 (75%) tumors and an average viability of 38% (5-68%). Heated MMC demonstrated efficacy in 7/16 (43.8%) tumors with an average treatment viability of 51% (17-92.3%). PTOs fabricated from distinct anatomic sites exhibited site-specific variability in treatment responses. PM PTOs exhibit patient and anatomic location treatment responses suggestive of underlying disease clonality. In PM organoids cisplatin is superior to MMC in HIPEC.

A blinded, placebo-controlled study on the clinical effects of vitamin E supplementation in dogs with osteoarthritis.

BACKGROUND: Vitamin E has a positive effect in the management of osteoarthritis in humans, and in a previous study of dogs. It has been suggested to decrease C-reactive protein concentrations and liver enzyme activities in humans and animals. OBJECTIVE: To assess the effect of vitamin E supplementation on lameness, pain, pain medication requirement, clinical pathology variables, and quality of life in large-breed dogs with naturally occurring osteoarthritis. ANIMALS: Fifty-seven client-owned dogs with naturally occurring osteoarthritis. METHODS: Dogs received either vitamin E or placebo for 90 days in a randomized, placebo-controlled, double-blinded, prospective clinical trial. Clinical lameness scores, pain medication requirements, and owner questionnaires were used to assess response to treatment every 30 days. Blood samples were collected at enrollment and at the end of the study period. RESULTS: Vitamin E administration did not improve pain, lameness, or quality of life as assessed by owners and veterinarians. Vitamin E supplementation did not decrease the requirement for rescue pain relief. No changes in clinical pathology variables were observed after 90 days of vitamin E supplementation. Body weight was negatively associated with the lameness scores and requirement for rescue pain relief. CONCLUSION: Vitamin E supplementation did not have any observable positive effects in dogs with naturally occurring osteoarthritis.

Limosilactobacillus reuteri DSM 17938 supplementation and SARS-CoV-2 specific antibody response in healthy adults: a randomized, triple-blinded, placebo-controlled trial.

Studies have shown that probiotics can decrease the symptoms of respiratory tract infections as well as increase antibody responses following certain vaccinations. We examined the effect of probiotic supplementation on anti-SARS-CoV-2 specific antibody responses upon SARS-CoV-2 infection as well as after COVID-19 vaccination. In this randomized, triple-blinded, placebo-controlled intervention study with a parallel design, 159 healthy adults without prior SARS-CoV-2 infection or COVID-19 vaccination and any known risk factors for severe COVID-19 were randomly allocated into two study arms. The active treatment arm consumed a probiotic product containing a minimum of 1 × 108 colony-forming units of Limosilactobacillus reuteri DSM 17938 + 10 µg vitamin D3 twice daily for 6 months. The placebo arm consumed identical tablets containing only 10 µg vitamin D3. Anti-SARS-CoV-2 specific antibodies and virus neutralizing antibody titers were analyzed from blood samples collected at baseline, after 3 months, and after 6 months. Differences in serum antibody titers between the two study arms were tested with independent t-test using log-transformed values. In the intention-to-treat (ITT) analysis, SARS-CoV-2 infected individuals in the active treatment arm (n = 6) tended to have higher serum anti-spike IgG (609 [168-1480] BAU/ml vs 111 [36.1-1210] BAU/ml, p = 0.080) and anti-receptor binding domain (RBD) IgG (928 [212-3449] BAU/ml vs (83.7 [22.8-2094] BAU/ml, p = 0.066) levels than individuals in the placebo arm (n = 6). Considering individuals who were fully vaccinated with mRNA-based COVID-19 vaccines, the active treatment arm (n = 10) exhibited significantly higher serum levels of anti-RBD IgA (135 [32.9-976] BAU/ml vs 61.3 [26.7-97.1] BAU/ml, p = 0.036) than the placebo arm (n = 7) >28 days postvaccination. Supplementation with specific probiotics might improve the long-term efficacy of mRNA-based COVID-19 vaccines via enhanced IgA response.

A Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver.

Regulatory T (Treg) cells modulate several aging-related liver diseases. However, the molecular mechanisms regulating Treg function in this context are unknown. Here we identified a long noncoding RNA, Altre (aging liver Treg-expressed non-protein-coding RNA), which was specifically expressed in the nucleus of Treg cells and increased with aging. Treg-specific deletion of Altre did not affect Treg homeostasis and function in young mice but caused Treg metabolic dysfunction, inflammatory liver microenvironment, liver fibrosis and liver cancer in aged mice. Depletion of Altre reduced Treg mitochondrial integrity and respiratory capacity, and induced reactive oxygen species accumulation, thus increasing intrahepatic Treg apoptosis in aged mice. Moreover, lipidomic analysis identified a specific lipid species driving Treg aging and apoptosis in the aging liver microenvironment. Mechanistically, Altre interacts with Yin Yang 1 to orchestrate its occupation on chromatin, thereby regulating the expression of a group of mitochondrial genes, and maintaining optimal mitochondrial function and Treg fitness in the liver of aged mice. In conclusion, the Treg-specific nuclear long noncoding RNA Altre maintains the immune-metabolic homeostasis of the aged liver through Yin Yang 1-regulated optimal mitochondrial function and the Treg-sustained liver immune microenvironment. Thus, Altre is a potential therapeutic target for the treatment of liver diseases affecting older adults.

The Global Forest Health Crisis: A Public-Good Social Dilemma in Need of International Collective Action.

Society is confronted by interconnected threats to ecological sustainability. Among these is the devastation of forests by destructive non-native pathogens and insects introduced through global trade, leading to the loss of critical ecosystem services and a global forest health crisis. We argue that the forest health crisis is a public-good social dilemma and propose a response framework that incorporates principles of collective action. This framework enables scientists to better engage policymakers and empowers the public to advocate for proactive biosecurity and forest health management. Collective action in forest health features broadly inclusive stakeholder engagement to build trust and set goals; accountability for destructive pest introductions; pooled support for weakest-link partners; and inclusion of intrinsic and nonmarket values of forest ecosystems in risk assessment. We provide short-term and longer-term measures that incorporate the above principles to shift the societal and ecological forest health paradigm to a more resilient state.

Pivotal Role of Genetic Counselors in the Uptake of Germline Genetic Testing in Non-Metastatic Breast Cancer and the Impact of Testing on Surgical Decision Making.

BACKGROUND: Genetic testing is increasingly utilized in breast cancer patients; however, testing rates remain low. We aimed to evaluate the rate of genetic testing at a tertiary academic medical center utilizing a multidisciplinary clinic model including genetic counselor. METHODS: A single-center retrospective chart review was performed on a cohort of newly diagnosed breast cancer patients from January 2018 through February 2019. Patients were reviewed for genetic screening eligibility, consultation with a genetic counselor, and test results. RESULTS: Final analysis included 426 patients. 261 (61.3%) were found to meet National Comprehensive Cancer Network guidelines for genetic testing, of which 178 patient (68.2%) underwent testing and 32 patients (12.3%) declined testing. Of the 165 not eligible for testing, 5 patients were tested. A total of 183 patients underwent testing and 116 (63.4%) had a negative result, 17 (9.3%) were positive for at least one gene mutation and 50 (27.3%) were identified to have a variant of unknown significance (VUS). There was a positive association between those patients who met with a genetic counselor and eligibility for testing (OR 31.1, 95% CI 16.0-60.5). CONCLUSIONS: Genetic testing result has become an increasingly important factor when defining optimal surgical treatment for breast cancer patients. Increasing the availability of genetic consultation for breast cancer patients can improve testing rates and patient selection.

Diurnal regulation of metabolism by Gs-alpha in hypothalamic QPLOT neurons.

Neurons in the hypothalamic preoptic area (POA) regulate multiple homeostatic processes, including thermoregulation and sleep, by sensing afferent input and modulating sympathetic nervous system output. The POA has an autonomous circadian clock and may also receive circadian signals indirectly from the suprachiasmatic nucleus. We have previously defined a subset of neurons in the POA termed QPLOT neurons that are identified by the expression of molecular markers (Qrfp, Ptger3, LepR, Opn5, Tacr3) that suggest receptivity to multiple stimuli. Because Ptger3, Opn5, and Tacr3 encode G-protein coupled receptors (GPCRs), we hypothesized that elucidating the G-protein signaling in these neurons is essential to understanding the interplay of inputs in the regulation of metabolism. Here, we describe how the stimulatory Gs-alpha subunit (Gnas) in QPLOT neurons regulates metabolism in mice. We analyzed Opn5cre; Gnasfl/fl mice using indirect calorimetry at ambient temperatures of 22°C (a historical standard), 10°C (a cold challenge), and 28°C (thermoneutrality) to assess the ability of QPLOT neurons to regulate metabolism. We observed a marked decrease in nocturnal locomotion of Opn5cre; Gnasfl/fl mice at both 28°C and 22°C, but no overall differences in energy expenditure, respiratory exchange, or food and water consumption. To analyze daily rhythmic patterns of metabolism, we assessed circadian parameters including amplitude, phase, and MESOR. Loss-of-function GNAS in QPLOT neurons resulted in several subtle rhythmic changes in multiple metabolic parameters. We observed that Opn5cre; Gnasfl/fl mice show a higher rhythm-adjusted mean energy expenditure at 22°C and 10°C, and an exaggerated respiratory exchange shift with temperature. At 28°C, Opn5cre; Gnasfl/fl mice have a significant delay in the phase of energy expenditure and respiratory exchange. Rhythmic analysis also showed limited increases in rhythm-adjusted means of food and water intake at 22°C and 28°C. Together, these data advance our understanding of Gαs-signaling in preoptic QPLOT neurons in regulating daily patterns of metabolism.