n-3 PUFA ameliorate functional outcomes following repetitive mTBI in the fat-1 mouse model.

Purpose: Repeated mild traumatic brain injuries (mTBI) are a continuing healthcare concern worldwide, given its potential for enduring adverse neurodegenerative conditions. Past research suggests a potential protective effect of n-3 polyunsaturated fatty acids (PUFA) in experimental models of mTBI. The aim of this study was to investigate whether the neuroprotective benefits of n-3 PUFA persist following repetitive weight drop injury (WDI). Methods: Male fat-1 mice (n = 12), able to endogenously convert n-6 PUFA to n-3 PUFA, and their wild type (WT) counterparts (n = 12) were maintained on a 10% w/w safflower diet. At 9-10 weeks of age, both groups received one mild low-impact WDI on the closed cranium daily, for three consecutive days. Following each WDI, time to righting reflex and seeking behaviour were measured. Neurological recovery, cognitive, motor, and neurobehavioural outcomes were assessed using the Neurological Severity Score (NSS) over 7 days (168 h) post-last WDI. Brains were assessed for cerebral microhemorrhages by Prussian blue and cellular damage by glial fibrillary acidic protein (GFAP) staining. Results: Fat-1 mice exhibited significantly faster righting reflex and seeking behaviour time, and lower mean NSS scores and at all post-WDI time points (p ≤ 0.05) compared to WT mice. Immunohistochemistry showed no significant difference in presence of cerebral microhemorrhage however, fat-1 mice had significantly lower GFAP staining in comparison to WT mice (p ≤ 0.05). Conclusion: n-3 PUFA is effective in restoring cognitive, motor, and behavioural function after repetitive WDI, which may be mediated through reduced cellular damage of the brain.

n-3 and n-6 Polyunsaturated Fatty Acids Modulate Macrophage-Myocyte Inflammatory Crosstalk and Improve Myocyte Insulin Sensitivity.

In obesity, circulating saturated fatty acids (SFAs) and inflammatory cytokines interfere with skeletal muscle insulin signaling, leading to whole body insulin resistance. Further, obese skeletal muscle is characterized by macrophage infiltration and polarization to the inflammatory M1 phenotype, which is central to the development of local inflammation and insulin resistance. While skeletal muscle-infiltrated macrophage-myocyte crosstalk is exacerbated by SFA, the effects of other fatty acids, such as n-3 and n-6 polyunsaturated fatty acids (PUFAs), are less studied. Thus, the objective of this study was to determine the effects of long-chain n-3 and n-6 PUFAs on macrophage M1 polarization and subsequent effects on myocyte inflammation and metabolic function compared to SFA. Using an in vitro model recapitulating obese skeletal muscle cells, differentiated L6 myocytes were cultured for 24 h with RAW 264.7 macrophage-conditioned media (MCM), followed by insulin stimulation (100 nM, 20 min). MCM was generated by pre-treating macrophages for 24 h with 100 µM palmitic acid (16:0, PA-control), arachidonic acid (20:4n-6, AA), or docosahexaenoic acid (22:6n-3, DHA). Next, macrophage cultures were stimulated with a physiological dose (10 ng/mL) of lipopolysaccharide for an additional 12 h to mimic in vivo obese endotoxin levels. Compared to PA, both AA and DHA reduced mRNA expression and/or secreted protein levels of markers for M1 (TNFα, IL-6, iNOS; p < 0.05) and increased those for M2 (IL-10, TGF-ß; p < 0.05) macrophage polarization. In turn, AA- and DHA-derived MCM reduced L6 myocyte-secreted cytokines (TNFα, IL-6; p < 0.05) and chemokines (MCP-1, MIP-1ß; p < 0.05). Only AA-derived MCM increased L6-myocyte phosphorylation of Akt (p < 0.05), yet this was inconsistent with improved insulin signaling, as only DHA-derived MCM improved L6 myocyte glucose uptake (p < 0.05). In conclusion, dietary n-3 and n-6 PUFAs may be a useful strategy to modulate macrophage-myocyte inflammatory crosstalk and improve myocyte insulin sensitivity in obesity.

Postoperative Activity Restrictions After Slings: A Randomized Controlled Trial.

IMPORTANCE: Restricting activity after midurethral slings is an unproven practice. OBJECTIVE: The objective of this study was to evaluate the effect of postoperative activity restriction on satisfaction and outcomes after slings. STUDY DESIGN: This was a multicenter, 2-arm, noninferiority randomized controlled trial. Patients aged 18-85 years undergoing treatment with a midurethral sling were randomized 1:1 to postoperative activity restriction or liberal activity. Restrictions included avoidance of strenuous exercise and heavy lifting. The liberal group was allowed to resume activity at their discretion. Our primary outcome was satisfaction with postoperative instruction at 2 weeks. Secondary outcomes included surgical failure, mesh exposure rates, and other adverse events. RESULTS: In total, 158 patients were randomized with 80 to the liberal group and 78 to the restricted group. At 2 weeks, 54 (80.6%) of patients in the liberal group and 48 (73.9%) of patients in the restricted group were satisfied. We found statistical evidence supporting the hypothesis that postoperative liberal activity instruction is noninferior to activity restriction with regard to patient satisfaction (P = 0.0281). There was no significant difference in strenuous activity at 2 weeks (P = 0.0824). The liberal group reported significantly more moderate activity at 2 weeks (P = 0.0384) and more strenuous activity at 6 weeks and 6 months (P = 0.0171, P = 0.0118, respectively). The rate of recurrent or persistent stress incontinence for liberal versus restricted groups was 18.52% versus 23.53% (P = 0.635). There were no statistically significant differences in complication rates. CONCLUSIONS: Postoperative liberal activity was noninferior to activity restriction with regard to patients' satisfaction. There was no evidence supporting a statistically significant association between postoperative instruction and negative surgical outcomes.

COVID-19 Vaccination Coverage, and Rates of SARS-CoV-2 Infection and COVID-19-Associated Hospitalization Among Residents in Nursing Homes - National Healthcare Safety Network, United States, October 2023-February 2024.

Nursing home residents are at increased risk for developing severe COVID-19. Nursing homes report weekly facility-level data on SARS-CoV-2 infections, COVID-19-associated hospitalizations, and COVID-19 vaccination coverage among residents to CDC's National Healthcare Safety Network. This analysis describes rates of incident SARS-CoV-2 infection, rates of incident COVID-19-associated hospitalization, and COVID-19 vaccination coverage during October 16, 2023-February 11, 2024. Weekly rates of SARS-CoV-2 infection ranged from 61.4 to 133.8 per 10,000 nursing home residents. The weekly percentage of facilities reporting one or more incident SARS-CoV-2 infections ranged from 14.9% to 26.1%. Weekly rates of COVID-19-associated hospitalization ranged from 3.8 to 7.1 per 10,000 residents, and the weekly percentage of facilities reporting one or more COVID-19-associated hospitalizations ranged from 2.6% to 4.7%. By February 11, 2024, 40.5% of nursing home residents had received a dose of the updated 2023-2024 COVID-19 vaccine that was first recommended in September 2023. Although the peak rate of SARS-CoV-2 infection among nursing home residents was lower during the 2023-24 respiratory virus season than during the three previous respiratory virus seasons, nursing home residents continued to be disproportionately affected by SARS-CoV-2 infection and related severe outcomes. Vaccination coverage remains suboptimal in this population. Ongoing surveillance for SARS-CoV-2 infections and COVID-19-associated hospitalizations in this population is necessary to develop and evaluate evidence-based interventions for protecting nursing home residents.

Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists.

G-protein-coupled receptor 84 (GPR84) is a proinflammatory orphan G-protein-coupled receptor implicated in several inflammatory and fibrotic diseases. Several agonist and antagonist ligands have been developed that target GPR84; however, a noncompetitive receptor blocker that was progressed to phase II clinical trials failed to demonstrate efficacy. New high-quality antagonists are required to investigate the pathophysiological role of GPR84 and to validate GPR84 as a therapeutic target. We previously reported the discovery of a novel triazine GPR84 competitive antagonist 1. Here, we describe an extensive structure-activity relationship (SAR) of antagonist 1 and also present in silico docking with supporting mutagenesis studies that reveals a potential binding pose for this type of orthosteric antagonist. Lead compound 42 is a potent GPR84 antagonist with a favorable pharmacokinetic (PK) profile suitable for further drug development.

Differential Effects of Short-Chain Fatty Acids on L6 Myotube Inflammatory Mediator Production in Response to Lipopolysaccharide- or Palmitic Acid-Stimulation.

Short-chain fatty acids (SCFA) produced from dietary non-digestible carbohydrate fermentation have metabolic effects in skeletal muscle; however, their effect on inflammatory mediator production is unknown. In this study, L6 myotubes were cultured with individual SCFA (acetate, propionate, and butyrate) at 0.5 mM and 2.5 mM ± 10 ng/mL lipopolysaccharide (LPS) or ± 500 µM palmitic acid (PA) for 24 h. In response to LPS, only butyrate had an effect at the lower concentration (0.5 mM), whereas at the higher concentration (2.5 mM) both propionate and butyrate reduced MCP-1, MIP-1α, and RANTES secretion (p < 0.05), and only butyrate reduced IL-6 secretion and intracellular protein levels of phospho-STAT3 (p < 0.05). In response to PA, 0.5 mM butyrate reduced protein expression of phospho-NFκB p65 and the secretion of IL-6, MIP-1α, and MCP-1, whereas all three SCFA reduced RANTES secretion (p < 0.05). At the 2.5 mM SCFA concentration combined with PA stimulation, all three SCFA reduced intracellular protein expression of phospho-NFκB p65 and phospho-STAT3 and secreted protein levels of MCP-1, IL-6, and RANTES, whereas only butyrate reduced secretion of MIP-1α (p < 0.05). Thus, SCFA exhibit differential effects on inflammatory mediator expression in response to LPS and PA stimulation, which has implications for their individual impacts on inflammation-mediated skeletal muscle dysfunction.

Imitation of ß-lactam binding enables broad-spectrum metallo-ß-lactamase inhibitors.

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-ß-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential ß-lactamase stable ß-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.

N-3 Polyunsaturated Fatty Acids Ameliorate Neurobehavioral Outcomes Post-Mild Traumatic Brain Injury in the Fat-1 Mouse Model.

Concussions and mild traumatic brain injury (m-TBI) have been identified as a consequential public health concern because of their potential to cause considerable impairments in physical, cognitive, behavioral, and social functions. Given their prominent structural and functional roles in the brain, n-3 polyunsaturated fatty acids (PUFA) have been identified as a potentially viable prophylactic agent that may ameliorate the deleterious effects of m-TBI on brain function. The purpose of the present pilot study was to investigate the effect of n-3 PUFA on neurologic function using a weight drop injury (WDI) model. Fat-1 mice, capable of synthesizing n-3 PUFA endogenously from n-6 PUFA, and their wild-type (WT) counterparts, were subjected to a mild low-impact WDI on the closed cranium, and recovery was evaluated using the neurological severity score (NSS) to assess the motor and neurobehavioral outcomes. In comparison to the WT mice, the fat-1 mice had a significantly (p ≤ 0.05) lower NSS at all time points post-WDI, and significantly greater neurological restoration measured as the time to first movement. Overall, these findings demonstrate the protective effect of n-3 PUFA against mild brain injury.

Semi-automated analysis of supraclavicular thermal images increases speed of brown adipose tissue analysis without increasing variation in results.

Interest in brown adipose tissue remains high a decade after it was determined to be present outside of the neonatal period. In vivo imaging, however, has remained a challenge due to the lack of a imaging modality suitable for large healthy-volunteer studies, post-prandial investigations and vulnerable groups, such as children. Infrared thermography is increasingly accepted as a valid, non-invasive and flexible alternative but there is a wide approach to analysis between different groups. Defining the region of interest with anatomical borders rather than using a simple polygon may have advantages in terms of consistency but makes image analysis slower, limiting some applications. Our novel semi-automated method, using a custom-built graphical user interface, allows an 86% improvement in speed of image analysis (54.9 (38.3-71.4) seconds/image) without increases in variation between analysers or with repeated analysis. The improved efficiency demonstrated makes feasible larger studies, longer imaging periods or increased image acquisition frequency, providing an opportunity to study novel features of brown adipose tissue function.

Dietary ω-3 polyunsaturated fatty acids modulate CD4+ T-cell subset markers, adipocyte antigen-presentation potential, and NLRP3 inflammasome activity in a coculture model of obese adipose tissue.

OBJECTIVES: Chronic low-grade inflammation in obesity is partly driven by inflammatory cross talk between adipocytes and interferon-γ-secreting CD4+ T-helper (Th)1 cells, a process we have shown may be mitigated by long-chain (LC) ω-3 polyunsaturated fatty acids (PUFAs). Our objective was to study pivotal mediators of interactions between Th1 cells and adipocytes as potential mechanisms underlying the antiinflammatory effects of LC ω-3 PUFAs. METHODS: Using an in vitro model, 3T3-L1 adipocytes were cocultured with purified splenic CD4+ T cells from C57BL/6 mice consuming one of two isocaloric high-fat (HF) diets (60% kcal fat), containing either 41.2% kcal from lard + 18.7% kcal from corn oil (control, HF) or 41.2% kcal from lard + 13.4% kcal from corn oil + 5.3% kcal from fish oil (HF+FO). Cocultures were stimulated for 48 h with lipopolysaccharide (10 ng/mL). RESULTS: Compared with HF cocultures, HF+FO reduced Th1-cell markers (including secreted interferon-γ) and increased Th2-cell markers, consistent with reduced expression of genes related to major histocompatibility complex II (P < 0.05). HF+FO also blunted markers of priming and activity of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome (P < 0.05). In confirmatory work, 3T3-L1 adipocyte pretreatment with the LC ω-3 PUFA docosahexaenoic acid (100 µM, 24 h) blunted interferon-γ-induced (5 ng/mL, 24 h) expression of genes related to major histocompatibility complex II and priming and activity markers of the NLRP3 inflammasome compared with control (P < 0.05). CONCLUSIONS: Inflammatory interactions between CD4+ T cells and adipocytes may provide a target for LC ω-3 PUFAs to mitigate obesity-associated inflammation.

Apple consumption reduces markers of postprandial inflammation following a high fat meal in overweight and obese adults: A randomized, crossover trial.

High fat meal-induced postprandial inflammation is exacerbated in overweight and obesity and may contribute to cardiovascular disease (CVD) risk. This study aimed to determine the effects of apples, rich in anti-inflammatory polyphenols, on biomarkers of postprandial inflammation in individuals with overweight and obesity. A randomized, crossover trial was conducted with n = 26 participants (17 female/9 male; mean age 45.5 ± 3.12 years; mean BMI 34.1 ± 1.18 kg m-2) to assess the effects of 3 whole Gala apples (∼200 g) on the 2, 4 and 6 h postprandial response to a high fat meal providing 1 g fat per kg body weight. Changes in plasma biomarkers of inflammation (as the primary outcome) and endotoxin exposure, non-esterified fatty acids (NEFA) and total antioxidant capacity (TAC) were measured. Fasting (0 h) and 4 h peripheral blood mononuclear cells (PBMC) were also isolated from whole blood and stimulated with or without a physiological dose (10 ng mL-1) of lipopolysaccharide (LPS) to measure secreted cytokines. Apples modulated postprandial plasma IFN-γ and reduced its peak concentration (-12.8%), and increased both 4 h (14.4%) and peak (10.5%) TAC (P < 0.05). In unstimulated and LPS-stimulated PBMC, apples reduced secreted IL-6 (-49.3% and -17.1%) and TNF-α (-43.3% and -14.7%) and increased IL-4 (93.1% and 15.8%) in both the unstimulated and LPS-stimulated conditions, as well as decreased GM-CSF (-26.0%) and IL-17 (-47.9%) in unstimulated PBMC and G-CSF (-19.8%) in LPS-stimulated PBMC (P < 0.05). These data suggest acute whole Gala apple consumption may be an effective dietary strategy to mitigate high fat meal-induced postprandial inflammation that exacerbates CVD risk in overweight and obesity. This study was registered at clinicaltrials.gov, NCT03523403, The Apple Study: Investigating the Effects of Whole Apple Consumption on Risk Factors for Chronic Metabolic Diseases in Overweight and Obese Adults.

Daily apple consumption reduces plasma and peripheral blood mononuclear cell-secreted inflammatory biomarkers in adults with overweight and obesity: a 6-week randomized, controlled, parallel-arm trial.

BACKGROUND: Obesity-associated low-grade inflammation contributes to the development of cardiovascular disease (CVD). Apples are rich in anti-inflammatory bioactives including polyphenols and fiber. OBJECTIVES: We aimed to determine the effects of regular apple consumption on fasting plasma biomarkers of inflammation (primary outcome), endotoxemia, carbohydrate and lipid metabolism (glucose, insulin, triacylglycerol; secondary outcomes), and peripheral blood mononuclear cell (PBMC)-secreted cytokines (secondary outcome) in individuals with overweight and obesity. METHODS: A randomized, controlled, parallel-arm trial was conducted with n = 46 participants. After avoiding foods and beverages rich in polyphenols and fiber for 2 wk, participants consumed 3 whole Gala apples (∼200 g edible parts)/d as part of their habitual diet (n = 23) or avoided apples (control, n = 23) for 6 wk. All participants limited consumption of polyphenols and fiber during the 6-wk trial. Fasting blood samples were collected before and after 6 wk for analysis of plasma biomarkers and isolation of PBMCs, which were cultured for 24 h unstimulated or stimulated with LPS (10 ng/mL). RESULTS: Forty-four participants completed the trial (30 female, 14 male; mean ± SEM age: 45.4 ± 2.2 y; BMI: 33.4 ± 0.9 kg/m2). After ANCOVA and correcting for multiple comparisons, apples decreased fasting plasma C-reactive protein by 17.0% (range: 14.3%-19.6%, P = 0.005), IL-6 by 12.4% (range: 6.7%-17.5%, P < 0.001), and LPS-binding protein by 20.7% (range: 14.1%-26.4%, P < 0.001) compared with control. Apples also decreased PBMC-secreted IL-6 by 28.3% (range: 22.4%-33.5%, P < 0.001) and IL-17 by 11.0% (range 5.8-15.6%, P = 0.003) in the unstimulated condition compared with control. Exploratory analysis showed apples also increased plasma total antioxidant capacity by 9.6% (range: 1.7-18.9%, P = 0.002) compared with control. However, apples had no effect on anthropometric or other CVD risk markers. CONCLUSIONS: Six-week daily whole Gala apple consumption may be an effective dietary strategy to mitigate the obesity-associated inflammation that exacerbates CVD risk, without weight loss. This trial was registered at clinicaltrials.gov as NCT03523403.

Fish oil supplementation increases expression of mammary tumor apoptosis mediators and reduces inflammation in an obesity-associated HER-2 breast cancer model.

Obesity is associated with inflammation and has been shown to increase breast cancer severity. The objective of this study was to examine the effect of fish oil (FO) supplementation in obesity-associated mammary tumorigenesis in the MMTV-neu(ndl)-YD5 mouse model of human epidermal growth factor receptor-2 positive BC. Female mice were fed one of three diets for 16 weeks: i) high fat diet [HF, % kacl: 41.2% lard, 18.7% corn oil (CO)], ii) an isocaloric HF plus menhaden FO diet (HF+FO, % kcal: 41.2 lard, 13.4% CO, 5.3% FO), iii) low fat diet (LF, % kcal: 4.7% lard, 6% CO). HF mice had increased body weight, visceral adipose weight and serum hormone concentrations (increased leptin and resistin; decreased adiponectin) versus LF, which was attenuated in the HF+FO group versus HF (P<.05). Compared to HF, tumor onset was delayed in HF+FO and LF mice (P<0.05). Compared to HF, HF+FO reduced mammary tumor multiplicity (-27%), tumor weight (-46%) and total tumor volume (-50%) (P<0.05). Additionally, HF+FO reduced mammary tumor multiplicity (-33%), tumor weight (-39%) and total tumor volume (-60%) versus LF. HF+FO improved mammary tumor apoptosis status with increased expression of pro-apoptotic Bad and decreased expression of anti-apoptotic Bcl-xLmediators versus HF (P<0.05). Additionally, HF+FO decreased tumor protein expression of activated Akt, NFκB p65 and STAT3, versus HF (P<0.05). Tumor mRNA expression of inflammatory mediators TNFα, IL-6 and leptin were reduced in HF+FO, whereas IL-10 expression was increased compared to HF (P<0.05). Collectively these results demonstrate the efficacy of FO supplementation for improving obesity-associated breast cancer outcomes.

Navy Bean Supplementation in Established High-Fat Diet-Induced Obesity Attenuates the Severity of the Obese Inflammatory Phenotype.

Cooked common beans (Phaseolus vulgaris) improve intestinal health in lean mice and attenuate intestinal dysbiosis and inflammation when consumed concurrent with obesity development. We determined the effects of a high-fat (HF) bean supplemented diet in mice with established obesity (induced by 12 weeks of HF diet (60% fat as kcal)) compared to obese mice consuming a HF or low-fat (LF) weight loss control diet. Obese C57BL/6 male mice remained consuming HF for eight weeks or were randomly switched from HF to an isocaloric HF with 15.7% cooked navy bean powder diet (HFàHFB) or LF (11% fat as kcal; HFàLF) (n = 12/group). HFàHFB improved the obese phenotype, including (i) fecal microbiome (increased Prevotella, Akkermansia muciniphila, and short-chain fatty acid levels), (ii) intestinal health (increased ZO-1, claudin-2, Muc2, Relmß, and Reg3γ expression), and (iii) reduced adipose tissue (AT) inflammatory proteins (NFκBp65, STAT3, IL-6, MCP-1, and MIP-1α), versus HF (p < 0.05). Conversely, HFàLF reduced body weight and circulating hormones (leptin, resistin, and PAI-1) versus HF and HFàHFB (p < 0.05); however, AT inflammation and intestinal health markers were not improved to the same degree as HFàHFB (p < 0.05). Despite remaining on a HF obesogenic diet, introducing beans in established obesity improved the obese phenotype (intestinal health and adipose inflammation) more substantially than weight loss alone.

Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness.

Bottlebrush polymers have great potential as vehicles to noncovalently sequester, stabilize, and deliver hydrophobic small molecule actives. To this end, we synthesized a poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) bottlebrush copolymer using ring-opening metathesis polymerization and developed a facile method to control the thermoresponsive properties using postpolymerization modification. Six increasingly hydrophilic end-groups were installed, yielding cloud point temperature control over a range of 22-42 °C. Solubility enhancement of the antiseizure medication, phenytoin, increased significantly with the hydrophilicity of the end-group moiety. Notably, carboxylated bottlebrush copolymers solubilized formulations with higher drug loadings than linear copolymers because they exist as unimolecular nanoparticles with a synthetically defined density of polymer chains that are more stable in solution. This work provides the first investigation of bottlebrush polymers for hydrophobic noncovalent sequestration and solubilization of pharmaceuticals.

Chemical and Mechanical Tunability of 3D-Printed Dynamic Covalent Networks Based on Boronate Esters.

As the scope of additive manufacturing broadens, interest has developed in 3D-printed objects that are derived from recyclable resins with chemical and mechanical tunability. Dynamic covalent bonds have the potential to not only increase the sustainability of 3D-printed objects, but also serve as reactive sites for postprinting derivatization. In this study, we use boronate esters as a key building block for the development of catalyst-free, 3D-printing resins with the ability to undergo room-temperature exchange at the cross-linking sites. The orthogonality of boronate esters is exploited in fast-curing, oxygen-tolerant thiol-ene resins in which the dynamic character of 3D-printed objects can be modulated by the addition of a static, covalent cross-linker with no room-temperature bond exchange. This allows the mechanical properties of printed parts to be varied between those of a traditional thermoset and a vitrimer. Objects printed with a hybrid dynamic/static resin exhibit a balance of structural stability (residual stress = 18%) and rapid exchange (characteristic relaxation time = 7 s), allowing for interfacial welding and postprinting functionalization. Modulation of the cross-linking density postprinting is enabled by selective hydrolysis of the boronate esters to generate networks with swelling capacities tunable from 1.3 to 3.3.

Reduced brown adipose tissue-associated skin temperature following cold stimulation in children and adolescents with type 1 diabetes.

BACKGROUND: Brown adipose tissue (BAT) is essential to maintain body temperature. Its ability to convert chemical energy in glucose and free fatty acids to heat is conferred by a unique protein, UCP-1. BAT activity is greatest in children and adolescents, declining through adulthood. Blood glucose concentrations outside the normal nondiabetic range are common in type 1 diabetes and hyperglycaemia leads to insulin resistance in muscle and white adipose tissue, but whether this applies to BAT, is not known. METHOD: To investigate the effect of type 1 diabetes on BAT activity, we measured the supraclavicular temperature of 20 children with type 1 diabetes and compared them to 20 age-matched controls, using infrared thermography. RESULTS: The diabetes group had lower stimulated supraclavicular temperatures (diabetes group: 35.03 (34.76-35.30)°C; control group: 35.42 (35.16-35.69)°C; p = 0.037) and a reduced response in relative temperature following cold stimulation, after adjusting for BMI (diabetes group: 0.11 (0.03-0.18)°C; control group: 0.22 (0.15-0.29)°C; p = 0.034). In the diabetes group, there was no association between glycaemic measures and supraclavicular temperatures, but the method of insulin delivery may significantly affect the change in supraclavicular temperature with stimulation (injections: 0.01 (-0.07-0.09)°C; pump: 0.15 (0.04-0.26)°C; p = 0.028). CONCLUSIONS: While further work is needed to better understand the glucose-insulin-BAT relationship, one possible explanation for the reduced supraclavicular temperature is that exogenous, unlike endogenous, insulin, is not suppressed by the activity of the sympathetic nervous system, preventing lipolysis-driven activation of BAT.

Plasma levels of platinum-induced fatty acid [16:4n-3] do not affect response to platinum-based chemotherapy: A pilot study in non-small cell lung cancer patients.

BACKGROUND & AIMS: Pre-clinical studies suggest that 16:4(n-3) in purified form or as a component of fish oil might induce platinum-based chemotherapy resistance. Our aim was to determine plasma total and free 16:4(n-3) before and during platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients supplemented with fish oil or provided standard care, and to explore relationships between plasma 16:4(n-3) levels and tumor response to treatment. METHODS: In a retrospective, secondary data analysis of a prior clinical trial, plasma from patients with NSCLC (n = 21) who underwent platinum-based chemotherapy and were assigned to 2.2 g/day of eicosapentaenoic (EPA) plus 1.1 g DHA/day as fish oil (FO; n = 12) or received no intervention (standard care; SC; n = 9). Plasma 16:4(n-3) was quantified as free and esterified (total) fatty acid using HPLC-MS/MS. Plasma 16:4(n-3) levels were evaluated over time in relation to fish oil supplementation and response to platinum-based therapy, and compared with a group of healthy subjects (REF; n = 11). RESULTS: Plasma 16:4(n-3) was detected in all samples. The percentage change/day in plasma esterified (total) 16:4(n-3) was higher for FO versus SC group (2.7 versus -1.8%/d, U = 20, p = 0.02), but change in plasma free 16:4(n-3) was not different between FO and SC. Median plasma free and esterified 16:4(n-3) were similar between responders and non-responders to platinum-based chemotherapy. Total and free plasma 16:4(n-3) fatty acids were similar between NSCLC patients and REF (NSCLC vs REF: total 16:4(n-3): 122.9 vs. 95.2 nM and free 16:4(n-3) 23.9 vs. 27.6 nM). CONCLUSIONS: This first of its kind study that evaluated plasma 16:4(n-3) in NSCLC patients showed that 16:4 (n-3) was elevated during FO supplementation, independent of fish oil supplementation or platinum-based chemotherapy.

The daytime feeding frequency affects appetite-regulating hormones, amino acids, physical activity, and respiratory quotient, but not energy expenditure, in adult cats fed regimens for 21 days.

The effects of feeding frequency on postprandial response of circulating appetite-regulating hormones, insulin, glucose and amino acids, and on physical activity, energy expenditure, and respiratory quotient were studied in healthy adult cats. Two experiments were designed as a 2 x 3 replicated incomplete Latin square design. Eight cats, with an average body weight (BW) of 4.34 kg ± 0.04 and body condition score (BCS) of 5.4 ± 1.4 (9 point scale), were fed isocaloric amounts of a commercial adult maintenance canned cat food either once (0800 h) or four times daily (0800 h, 1130 h, 1500 h, 1830 h). Study 1 consisted of three 21-d periods. On day 14, two fasted and 11 postprandial blood samples were collected over 24 hours to measure plasma concentrations of ghrelin, GLP-1, GIP, leptin, PYY, insulin and amino acids, and whole blood glucose. Physical activity was monitored from day 15 to 21 of each period. In Study 2 indirect calorimetry was performed on the last day of each period. Body weight was measured weekly and feed intake recorded daily in both experiments. No effect of feeding regimen on BW was detected. Cats eating four times daily had lesser plasma concentrations of GIP and GLP-1 (P<0.05) and tended to have lesser plasma PYY concentrations (P<0.1). Plasma leptin and whole blood glucose concentrations did not differ between regimens (P>0.1). Cats fed once daily had a greater postprandial plasma amino acid response, and greater plasma ghrelin and insulin concentrations (P<0.05). Physical activity was greater in cats fed four times (P<0.05), though energy expenditure was similar between treatments at fasting and in postprandial phases. Finally, cats eating one meal had a lower fasting respiratory quotient (P<0.05). Overall, these data indicate that feeding once a day may be a beneficial feeding management strategy for indoor cats to promote satiation and lean body mass.