Micronutrient, Metabolic, and Inflammatory Biomarkers through 24 Months of Age in Infants Receiving Formula with Added Bovine Milk Fat Globule Membrane through the First Year of Life: A Randomized Controlled Trial.

BACKGROUND: Bovine milk fat globule membrane (MFGM) added in infant formula supports typical growth and safety through 24 mo of age in term infants. OBJECTIVES: To assess micronutrient (zinc, iron, ferritin, transferrin receptor), metabolic [glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), insulin-like growth factor-1 (IGF-1), triglycerides (TGs), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)], and inflammatory (leptin, adiponectin, high sensitivity C-reactive protein) secondary outcomes through 24 mo of age in infants who received standard cow's milk-based infant formula (SF), similar formula with added bovine MFGM (EF), or human milk (HM) through 1 y. METHODS: Infants whose parents agreed to a blood draw at baseline (<120 d of age) (SF = 80; EF = 80; HM = 83) were included. Subsequent collections (2-4 h fasting) occurred at D180, D365, and D730. Biomarker concentrations were analyzed and group changes tested using generalized estimating equations models. RESULTS: Only serum iron (+22.1 µg/dL) and HDL-C (+2.5 mg/dL) were significantly higher for EF compared with SF at D730. Prevalence of zinc deficiency for EF (-17.4%) and SF (-16.6%) at D180 and depleted iron stores for SF (+21.4%) at D180 and EF (-34.6%) and SF (-28.0%) at D365 were significantly different compared with HM. IGF-1 (ng/mL) for EF and SF was significantly higher at D180 (+8.9) and for EF (+8.8) at D365, and (+14.5) at D730 compared with HM. Insulin (µUI/mL) for EF (+2.5) and SF (+5.8) and HOMA-IR for EF (+0.5) and SF (+0.6) were significantly higher compared with HM at D180. TGs (mg/dL) for SF (+23.9) at D180, for EF (+19.0) and SF (+17.8) at D365, and EF (+17.3) and SF (+14.5) at D730 were significantly higher compared with HM. Zinc, ferritin, glucose, LDL-C and total cholesterol changes were higher in formula groups compared with HM between various time points. CONCLUSIONS: Micronutrient, metabolic, and inflammatory biomarkers were generally similar through 2 y in infants who received infant formula with or without added bovine MFGM. Over the 2 y, differences were observed between infant formulas and HM reference group. This trial was registered at clinicaltrials.gov as NTC02626143.

Germline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have dramatically improved survival in patients with cancer but are often accompanied by severe immune-related adverse events (irAEs), which can sometimes be irreversible. Insulin-dependent diabetes is a rare, but life-altering irAE. Our purpose was to determine whether recurrent somatic or germline mutations are observed in patients who develop insulin-dependent diabetes as an irAE. METHODS: We performed RNA and whole exome sequencing on tumors from 13 patients who developed diabetes due to ICI exposure (ICI-induced diabetes mellitus, ICI-DM) compared with control patients who did not develop diabetes. RESULTS: In tumors from ICI-DM patients, we did not find differences in expression of conventional type 1 diabetes autoantigens, but we did observe significant overexpression of ORM1, PLG, and G6PC, all of which have been implicated in type 1 diabetes or are related to pancreas and islet cell function. Interestingly, we observed a missense mutation in NLRC5 in tumors of 9 of the 13 ICI-DM patients that was not observed in the control patients treated with the same drugs for the same cancers. Germline DNA from the ICI-DM patients was sequenced; all NLRC5 mutations were germline. The prevalence of NLRC5 germline variants was significantly greater than the general population (p=5.98×10-6). Although NLRC5 is implicated in development of type 1 diabetes, germline NLRC5 mutations were not found in public databases from patients with type 1 diabetes, suggesting a different mechanism of insulin-dependent diabetes in immunotherapy-treated patients with cancer. CONCLUSIONS: Validation of the NLRC5 mutation as a potential predictive biomarker is warranted, as it might improve patient selection for treatment regimens. Furthermore, this genetic alteration suggests potential mechanisms of islet cell destruction in the setting of checkpoint inhibitor therapy.

Impact of abdominal obesity on the risk of glioma development in patients with diabetes: A nationwide population-based cohort study in Korea.

BACKGROUND: Abdominal obesity has been suggested as a risk factor for glioma; however, it is unclear whether this association applies to people with diabetes. This study examined the association between abdominal obesity and the risk of developing gliomas in diabetic patients. METHODS: We conducted a retrospective cohort study using the National Health Insurance System of South Korea from 2009 to 2012. The primary outcome was the incidence of newly diagnosed gliomas according to waist circumference (WC), and subgroup analyses were performed according to demographic characteristics and diabetes status including disease duration, number of oral hypoglycemic agents, and insulin use. RESULTS: Of a total of 1,893,057 participants, 1,846 (0.10%) cases of gliomas occurred. After adjusting for confounding factors, WC ≥90 cm (men)/85 cm (women) was associated with significantly higher risks of gliomas (adjusted HR [95% CI]; 1.279 [1.053, 1.554], 1.317 [1.048, 1.655], and 1.369 [1.037, 1.807] in the WC <95 cm (men)/90 cm (women) group, WC <100 cm (men)/95 cm (women) group, and WC ≥100 cm (men)/95 cm (women) group, respectively). Subgroup analysis showed that patients with larger WC had a consistently higher incidence of glioma than their lean counterparts, except for insulin users (insulin user vs. nonuser, P for interaction = .03). CONCLUSIONS: Abdominal obesity was associated with the development of gliomas in diabetic patients in a nationwide population-based database. Further study is needed in diabetic patients to stratify the risk for glioma development according to WC and to establish the underlying mechanism of carcinogenesis.

Novel therapeutic approaches based on the pathological role of gut dysbiosis on the link between nonalcoholic fatty liver disease and insulin resistance.

The growing global epidemic of obesity and type 2 diabetes mellitus has determined an increased prevalence of NAFLD (non-alcoholic fatty liver disease), making it the most common chronic liver disease in the Western world and a leading cause of liver transplantation. In the last few years, a rising number of studies conducted both on animal and human models have shown the existence of a close association between insulin resistance (IR), dysbiosis, and steatosis. However, all the mechanisms that lead to impaired permeability, inflammation, and fibrosis have not been fully clarified. Recently, new possible treatment modalities have received much attention. To reach the review purpose, a broad-ranging literature search on multidisciplinary research databases was performed using the following terms alone or in combination: "NAFLD", "gut dysbiosis", "insulin resistance", "inflammation", "probiotics", "Chinese herbs". The use of probiotics, prebiotics, symbiotics, postbiotics, fecal microbiota transplant (FMT), Chinese herbal medicine, antibiotics, diet (polyphenols and fasting diets), and minor therapies such as carbon nanoparticles, the MCJ protein, water rich in molecular hydrogen, seems to be able to improve the phenotypic pattern in NAFLD patients. In this review, we provide an overview of how IR and dysbiosis contribute to the development and progression of NAFLD, as well as the therapeutic strategies currently in use.

4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes.

BACKGROUND: Pancreatic beta cell dysfunction and activated macrophage infiltration are early features in type 1 diabetes pathogenesis. A tricarboxylic acid cycle metabolite that can strongly activate NF-E2-related factor 2 (Nrf2) in macrophages, itaconate is important in a series of inflammatory-associated diseases via anti-inflammatory and antioxidant properties. However, its role in type 1 diabetes is unclear. We used 4-octyl itaconate (OI), the cell-permeable itaconate derivate, to explore its preventative and therapeutic effects in mouse models of type 1 diabetes and the potential mechanism of macrophage phenotype reprogramming. METHODS: The mouse models of streptozotocin (STZ)-induced type 1 diabetes and spontaneous autoimmune diabetes were used to evaluate the preventative and therapeutic effects of OI, which were performed by measuring blood glucose, insulin level, pro- and anti-inflammatory cytokine secretion, histopathology examination, flow cytometry, and islet proteomics. The protective effect and mechanism of OI were examined via peritoneal macrophages isolated from STZ-induced diabetic mice and co-cultured MIN6 cells with OI-pre-treated inflammatory macrophages in vitro. Moreover, the inflammatory status of peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients was evaluated after OI treatment. RESULTS: OI ameliorated glycemic deterioration, increased systemic insulin level, and improved glucose metabolism in STZ-induced diabetic mice and non-obese diabetic (NOD) mice. OI intervention significantly restored the islet insulitis and beta cell function. OI did not alter the macrophage count but significantly downregulated the proportion of M1 macrophages. Additionally, OI significantly inhibited MAPK activation in macrophages to attenuate the macrophage inflammatory response, eventually improving beta cell dysfunction in vitro. Furthermore, we detected higher IL-1ß production upon lipopolysaccharide stimulation in the PBMCs from type 1 diabetes patients, which was attenuated by OI treatment. CONCLUSIONS: These results provided the first evidence to date that OI can prevent the progression of glycemic deterioration, excessive inflammation, and beta cell dysfunction predominantly mediated by restricting macrophage M1 polarization in mouse models of type 1 diabetes.

Mid-career switch nursing students' perceptions and experiences of using immersive virtual reality for clinical skills learning: A mixed methods study.

BACKGROUND: There has been an increase of mid-career professionals joining nursing. These adult students possess significant expertise in other areas and may benefit substantially in deliberate practice to acquire skills competency using immersive virtual reality (IVR) for clinical procedures before they practise in actual clinical settings. OBJECTIVES: This study aims to (1) examine the impact of IVR clinical procedures on mid-career switch students in knowledge, game perception and user reaction; (2) to explore the mid-career switch students' perceptions and experiences in using the IVR clinical procedures. DESIGN: A mixed methods feasibility study was used. SETTING AND PARTICIPANTS: This study was conducted at a university in Singapore with 34 first-year mid-career switch students. METHODS: This study is a single-group pre-test and post-test experimental study on learning clinical procedures using IVR in the home setting. The study took place from September to November 2021. Focus group discussions were conducted and analysed verbatim using thematic analysis. RESULTS: The students demonstrated significant improvement of knowledge for subcutaneous insulin, but overall, the increase in combined scores for both intravenous therapy and subcutaneous insulin were not statistically significant. Three overarching themes included: 1) Learning and practice, 2) Challenges and barriers, and 3) Personal attributes. Most of the participants found the experiences to be engaging, relevant, and satisfying. Some reported experiencing giddiness, headache, and lack of familiarity with technologies. CONCLUSIONS: IVR simulation can potentially be used as a supplementary learning tool to improve knowledge of clinical procedures in mid-career switch students.

Prevalence of comorbid depression and associated factors among hospitalized patients with type 2 diabetes mellitus in Hunan, China.

BACKGROUND: Depression and diabetes are major health challenges, with heavy economic social burden, and comorbid depression in diabetes could lead to a wide range of poor health outcomes. Although many descriptive studies have highlighted the prevalence of comorbid depression and its associated factors, the situation in Hunan, China, remains unclear. Therefore, this study aimed to identify the prevalence of comorbid depression and associated factors among hospitalized type 2 diabetes mellitus (T2DM) patients in Hunan, China. METHODS: This cross-sectional study involved 496 patients with T2DM who were referred to the endocrinology inpatient department of Xiangya Hospital affiliated to Central South University, Hunan. Participants' data on socio-demographic status, lifestyle factors, T2DM-related characteristics, and social support were collected. Depression was evaluated using the Hospital Anxiety and Depression Scale-depression subscale. All statistical analyses were conducted using the R software version 4.2.1. RESULTS: The prevalence of comorbid depression among hospitalized T2DM patients in Hunan was 27.22% (95% Confidence Interval [CI]: 23.3-31.1%). Individuals with depression differed significantly from those without depression in age, educational level, per capita monthly household income, current work status, current smoking status, current drinking status, regular physical activity, duration of diabetes, hypertension, chronic kidney disease, stroke, fatty liver, diabetic nephropathy, diabetic retinopathy, insulin use, HbA1c, and social support. A multivariable logistic regression model showed that insulin users (adjusted OR = 1.86, 95% CI: 1.02-3.42) had a higher risk of depression, while those with regular physical activity (adjusted OR = 0.48, 95% CI: 0.30-0.77) or greater social support (adjusted OR = 0.20, 95% CI: 0.11-0.34) had a lower risk of depression. The area under the curve of the receiver operator characteristic based on this model was 0.741 with a sensitivity of 0.785 and specificity of 0.615. CONCLUSIONS: Depression was moderately prevalent among hospitalized T2DM patients in Hunan, China. Insulin treatment strategies, regular physical activity, and social support were significantly independently associated with depression, and the multivariable model based on these three factors demonstrated good predictivity, which could be applied in clinical practice.

Childhood adiposity and novel subtypes of diabetes in adults: a Mendelian randomisation and genome-wide genetic correlation study.

BACKGROUND: Five novel subtypes of adult-onset diabetes were identified in 2018. We aimed to investigate whether childhood adiposity increases the risks of these subtypes using a Mendelian randomisation design, and to explore genetic overlaps between body size (self-reported perceived body size [ie, thinner, about average, or plumper] in childhood, and BMI measured in adulthood) and these subtypes. METHODS: The Mendelian randomisation and genetic correlation analyses were based on summary statistics from European genome-wide association studies of childhood body size (n=453 169), adult BMI (n=359 983), latent autoimmune diabetes in adults (n=8581), severe insulin-deficient diabetes (n=3937), severe insulin-resistant diabetes (n=3874), mild obesity-related diabetes (n=4118), and mild age-related diabetes (n=5605). We identified 267 independent genetic variants as instrumental variables for childhood body size in the Mendelian randomisation analysis of latent autoimmune diabetes in adults and 258 independent genetic variants as instrumental variables for other diabetes subtypes. The inverse variance-weighted method was used as the primary estimator in the Mendelian randomisation analysis, supplemented by other Mendelian randomisation estimators. We calculated overall genetic correlations (rg) between childhood or adult adiposity and different subtypes using linkage disequilibrium score regression. FINDINGS: A large childhood body size was associated with increased risk of latent autoimmune diabetes in adults (odds ratio [OR] 1·62, 95% CI 1·95-2·52), severe insulin-deficient diabetes (OR 2·45, 1·35-4·46), severe insulin-resistant diabetes (OR 3·08, 1·73-5·50), and mild obesity-related diabetes (OR 7·70, 4·32-13·7), but not mild age-related diabetes in the main Mendelian randomisation analysis. Other Mendelian randomisation estimators gave similar results and did not support the existence of horizontal pleiotropy. There was genetic overlap between childhood body size and mild obesity-related diabetes (rg 0·282; p=0·0003), and between adult BMI and all diabetes subtypes. INTERPRETATION: This study provides genetic evidence that higher childhood adiposity is a risk factor for all subtypes of adult-onset diabetes, except mild age-related diabetes. It is therefore important to prevent and intervene in childhood overweight or obesity. There is shared genetic contribution to childhood obesity and mild obesity-related diabetes. FUNDING: The study was supported by the China Scholarship Council, the Swedish Research Council (grant number 2018-03035), Research Council for Health, Working Life and Welfare (grant number 2018-00337), and Novo Nordisk Foundation (grant number NNF19OC0057274).

[The mechanisms of glucose transporter type 4 translocation regulated by insulin receptor signaling].

Insulin-regulated glucose transport is dependent on glucose transporter GLUT4 translocation to the plasma membrane, which incorporates glucose into the cells, mainly in adipose tissue and skeletal muscle. Insulin receptor signaling can stimulate GLUT4 vesicle transport from perinuclear pool to the plasma membrane via the vesicle transport machinery. At first, insulin signaling is divided to the multiple pathways, such as Akt/PKB and PKC-zeta/lambda. Subsequently, PKC-zeta/lambda activates KIF3, motor protein based on microtubules, and sequentially Akt/PKB activates Myosin-Va, motor protein based on actin filaments. KIF3 motor moves GLUT4 vesicles from perinuclear pool to the end of microtubules, and Myosin-Va transports GLUT4 vesicles from the end of microtubules to the plasma membrane. Here we indicate the machinery of insulin-regulated GLUT4 vesicle translocation, showing that these motor proteins are the destinations of insulin receptor signaling to regulate glucose transport into the cells.

Effect of a 1-year tailored exercise program according to cancer trajectories in patients with breast cancer: study protocol for a randomized controlled trial.

BACKGROUND: Patients with breast cancer undergo various treatments according to their tumor subtype and cancer stages within 1 year after being diagnosed. Each treatment may cause treatment-related symptoms that have negative impacts on patients' health and quality of life (QoL) The symptoms can be mitigated when exercise interventions are appropriately applied to patients' physical and mental conditions. Although many exercise programs were developed and implemented during this period, the effects of tailored exercise programs according to symptoms and cancer trajectories on patients' long-term health outcomes have not yet been fully elucidated. Therefore, this randomized controlled trial (RCT) aims to investigate the effect of tailored home-based exercise programs on short-term and long-term physiological outcomes in patients with breast cancer. METHODS: This 12-month RCT includes 96 patients with (stages 1-3) breast cancer randomly assigned to the exercise or control groups. Participants in the exercise group will receive an exercise program tailored to their phase of treatment, type of surgery, and physical function. During post-operative recovery, exercise interventions will be emphasized to improve shoulder range of motion (ROM) and strength. During chemoradiation therapy, exercise intervention will focus on improving physical function and preventing loss of muscle mass. Once chemoradiation therapy is completed, exercise intervention will focus on improving cardiopulmonary fitness and insulin resistance. All interventions will be home-based exercise programs supplemented with once-monthly exercise education and counseling sessions. The main outcome of the study is fasting insulin level at baseline, 6 months, and 1 year post-intervention. Our secondary outcomes include shoulder ROM and strength at 1 month and 3 months, body composition, inflammatory markers, microbiome, QoL, and physical activity levels at 1 month, 6 months, and 1 year post-intervention. CONCLUSION: This trial is the first tailored home-based exercise oncology trial to better understand the comprehensive phase-dependent short- and long-term effects of exercise on shoulder function, body composition, fasting insulin, biomarkers, and microbiome. The results of this study will inform the development of effective exercise programs tailored to the needs of patients with breast cancer post-operatively. TRIAL REGISTRATION: The protocol for this study is registered with the Korean Clinical Trials Registry (KCT0007853).

The Strategies of Development of New Non-Toxic Inhibitors of Amyloid Formation.

In recent years, due to the aging of the population and the development of diagnostic medicine, the number of identified diseases associated with the accumulation of amyloid proteins has increased. Some of these proteins are known to cause a number of degenerative diseases in humans, such as amyloid-beta (Aß) in Alzheimer's disease (AD), α-synuclein in Parkinson's disease (PD), and insulin and its analogues in insulin-derived amyloidosis. In this regard, it is important to develop strategies for the search and development of effective inhibitors of amyloid formation. Many studies have been carried out aimed at elucidating the mechanisms of amyloid aggregation of proteins and peptides. This review focuses on three amyloidogenic peptides and proteins-Aß, α-synuclein, and insulin-for which we will consider amyloid fibril formation mechanisms and analyze existing and prospective strategies for the development of effective and non-toxic inhibitors of amyloid formation. The development of non-toxic inhibitors of amyloid will allow them to be used more effectively for the treatment of diseases associated with amyloid.

Ingestion of whey protein and ß-conglycinin exerts opposite effects on intestinal FGF15 and serotonin secretion in mice.

Farnesoid X receptor (FXR) and Takeda G protein-coupled Receptor 5 (TGR5), the intestinal bile acid (BA) receptors, regulate the gut-derived hormones including fibroblast growth factor 15/19 (FGF15/19) and serotonin (5-hydrooxytryptamine, 5-HT). Here we show that ingestion of whey protein isolate, a milk protein, significantly decreased expression of heteromeric organic solute transporter Ostα and Ostß, which is the basolateral BA transporter in the enterocyte, and increased the expression of FXR and FGF15 in C57BL6J mouse ileum and plasma FGF15 levels. In addition, the ingestion of whey protein isolate significantly suppressed expression of hepatic cholesterol-7α hydroxylase (CYP7A1), which induces the primary BA synthesis, bile salt export pump (BSEP) and sodium-taurocholate cotransporting polypeptide (NTCP), which are the key transporters for the BA excretion and uptake in the liver, and genes involved in gluconeogenesis, and decreased the primary BAs including cholic acid, taurocholic acid, glycocholic acid, and taurochenodeoxycholic acid in the liver compared with controls. Moreover, ingestion of whey protein isolate significantly decreased the expression of TGR5, glucagon-like peptide 1 (GLP-1), and tryptophan hydroxylase1 (Tph1) in the small intestine, leading to decreases in plasma 5-HT and insulin levels. On the other hand, ingestion of the soy protein ß-conglycinin significantly increased the expression of Ostα and Ostß, and decreased the expression of FGF15 in the ileum and plasma FGF15 levels, leading to the increases in expression of hepatic CYP7A1, BSEP, NTCP, and genes involved in gluconeogenesis, and the primary BAs in the liver. Moreover, ingestion of ß-conglycinin significantly increased the expression of intestinal TGR5, GLP-1, and Tph1, leading to increases in plasma 5-HT and insulin levels. These findings suggest that whey protein and ß-conglycinin have opposite effects on intestinal FGF15 and 5-HT secretion in mice.

Modulation of AMPK/ TET2/ 5-hmC axis in response to metabolic alterations as a novel pathway for obesity-related colorectal cancer development.

Obesity is a major risk factor for colorectal cancer (CRC). Sustained hyperglycemia destabilizes tumor suppressor ten-eleven translocation (TET) 2, which is a substrate of AMPK, thereby dysregulating 5-hydroxymethylcytosine (5-hmC). However, the role played by this novel pathway in the development of obesity-related CRC is unclear. In this study, we aimed to evaluate the expression levels of TET2 and 5-hmC in obesity-related CRC and the effects of TET2 expression on the proliferation of CRC cells. To this end, surgically resected CRC samples from seven obese patients (Ob-CRC) and seven non-obese patients (nOb-CRC) were analyzed, and expression levels of the TET family and 5-hmC were compared between the groups. A decrease was observed in TET2 mRNA levels and 5-hmC levels in Ob-CRC compared to that in nOb-CRC. Furthermore, we used CRC cell lines to investigate the relationship between insulin, proliferation, and TET expression and AMPK. In cell lines, glucose and insulin treatments suppressed the expression of TET2 and increased cell proliferation. Downregulation of TET2 using siRNA also induced cell proliferation. An AMPK activator inhibited insulin- or glucose-stimulated cell proliferation and restored TET2 expression. We propose the AMPK-TET2-5-hmC axis as a novel pathway and potential therapeutic target in obesity-related CRC development.

Affinity-based protein profiling-driven discovery of myricanol as a Nampt activator.

Herein, we synthesized an affinity-based probe of myricanol (pMY) with a photo-affinity cross-linker to initiate a bioconjugation reaction, which was applied for target identification in live C2C12 myotubes. Pull-down of biotinylated pMY coupled with mass spectroscopy and Western blotting revealed that pMY can bind with nicotinamide phosphoribosyltransferase (Nampt), a rate-limiting enzyme in the nicotinamide adenine dinucleotide salvage pathway. Cellular thermal shift assay, drug affinity responsive target stability assay and recombinant protein labeling further validated the direct interaction between myricanol and Nampt. Myricanol did not affect the protein expression of Nampt, but enhanced its activity. Knock-down of Nampt totally abolished the promoting effect of myricanol on insulin-stimulated glucose uptake in C2C12 myotubes. Taken together, myricanol sensitizes insulin action in myotubes through binding with and activating Nampt.

Pediatric Resident Insulin Management Education (PRIME): A Single-Session Workshop Emphasizing Active Learning.

Introduction: Insulin is a high-risk medication, and errors can lead to patient morbidity and mortality. The American Board of Pediatrics recommends that all board-certified pediatricians be able to develop an insulin management plan for patients with diabetes. A needs assessment of pediatric residents revealed low self-efficacy at developing a new subcutaneous insulin plan despite didactic instruction on the topic. Methods: We created a 90-minute interactive workshop that targeted resident skills in devising subcutaneous insulin plans. Learners engaged in small-group, problem-based learning and peer teaching to promote active learning and participation. We compared self-efficacy and knowledge before and after the intervention using paired t tests and evaluated learner satisfaction. Results: Twenty-eight pediatric interns participated, with 25 completing both the pre- and postworkshop surveys. The primary outcome was self-efficacy (an individual's confidence in the ability to perform a specific task in a given domain). There was a statistically significant improvement in self-efficacy at creating a new subcutaneous insulin plan ( p < .001) as well as knowledge ( p < .001) after course completion. Learners were highly satisfied with the course, with a mean overall conference quality rating of 4.8 (SD = 0.4) based on a 5-point Likert scale (1 = poor, 5 = outstanding). Discussion: An interactive workshop employing active learning methods resulted in improved self-efficacy and knowledge in first-year pediatric residents. Future work is needed to determine the impact of this workshop on patient care outcomes.

Oral Microbiota-One Habitat or Diverse Niches? A Pilot Study of Sampling and Identification of Oral Bacterial and Fungal Biota in Patients with Type I Diabetes Mellitus Treated with Insulin Pump.

OBJECTIVE: The oral microbiota is a very complex and dynamic microbial ecosystem. Alterations of its balance can result in oral and systemic diseases. We aimed to characterize the microbiota in particular niches of the oral cavity in adult type 1 diabetes patients treated with continuous infusion of insulin with insulin pump (IP). In addition, we aimed to determine optimal sites of oral microbiota sampling in studies of large research groups of patients with DM I. DESIGN: In this pilot study, we sampled the buccal and soft palate mucosa, tongue, palatal and buccal dental surfaces and gingival pockets of adult DM I patients treated with IP. RESULTS: In total, 23 patients were recruited. The oral microbiota was dominated by Streptococus and Neisseria, with a low incidence of cariogenic S. mutans and Lactobacillus, as well as periodontal pathogens such as Prevotella. There were significant differences in overall CFU counts of all strains, Gram-positive, Staphylococci, Streptococci and S. oralis strains between mucosal and dental surface sites. The overall CFU counts of all strains and Gram-positive strains were higher in dental sites vs. mucosal sites (both p < 0.001). CFU counts of S. oralis were significantly higher in dental sites vs. gingival pocket sites (p = 0.013). Candida species were rare. The mucosal sites on the buccae presented lower diversity and bacterial counts. CONCLUSIONS: In the study group of adult DM I patients treated with IP, the microbiota in particular niches of the oral cavity was significantly different. Three distinct and optimally appropriate sampling sites for oral microflora were identified: buccal and palatal mucosa, dental surface and gingival pockets. The results of this study may be the basis for further studies of large groups of patients with DM I.

Associations between insulin-like factor 3, scrotal circumference and semen characteristics in young Norwegian Red bulls.

With the integration of genomic selection in the cattle artificial insemination (AI) industry, bulls are selected for their semen production capacity and fertility at a younger age than previously. Norwegian Red bull calves selected as candidates to become future AI bulls based on their genomic breeding value are kept in a performance testing station from around the age of 3-12 months, allowing for sample collection and analysis of different parameters during their pre- and peripubertal period. Insulin-like factor 3 (INSL3) is a small peptide hormone specifically secreted by the mature Leydig cells of the testes. In the foetus, it induces the first phase of testicular descent and is considered to reflect Leydig cell development during puberty; it could therefore be an interesting early indicator of future semen production capacity. The main objective of our study was to evaluate the relationship between INSL3, scrotal circumference (SC), and semen characteristics. This is the first time INSL3 was measured in the Norwegian Red population. We collected blood samples for analysis of INSL3 from 142 Norwegian Red bulls at the performance testing station and measured their SC on the same day. Altogether, measurements were made at four time points: upon arrival at the performance testing station (quarantine (Q): 2-5 months) and later at approximately 6, 9 and 12 months of age. Information on season and place of birth were made available from the database of the breeding company Geno, together with data on semen characteristics from the test station and the AI station. The median SCs for age groups Q, 6, 9, and 12 were 15, 21.5, 29, and 34 cm, respectively. INSL3 was shown to be positively correlated with SC (R = 0.4) but not with any of the semen characteristics. Similarly, we found no correlation between SC and sperm characteristics from data on ejaculates analysed at the performance testing station and AI station. The mean sperm volume for the 31 selected bulls with at least 10 ejaculates produced in the AI station increased from 2.3 ml at the performance testing station to 6.4 ml at the AI station. The corresponding increase in mean sperm concentration was from 497 million/ml to 1 049 million/ml. We conclude that INSL3 exhibits high inter-individual variability in the Norwegian Red bull population, which cannot be explained by the parameters measured in this study. At present, INSL3 cannot be used as a biomarker of sperm production in this breed.

Diagnostic Significance of hsa-miR-21-5p, hsa-miR-192-5p, hsa-miR-155-5p, hsa-miR-199a-5p Panel and Ratios in Hepatocellular Carcinoma on Top of Liver Cirrhosis in HCV-Infected Patients.

Early hepatocellular carcinoma (HCC) diagnosis is challenging. Moreover, for patients with alpha-fetoprotein (AFP)-negative HCC, this challenge is augmented. MicroRNAs (miRs) profiles may serve as potential HCC molecular markers. We aimed to assess plasma homo sapiens-(hsa)-miR-21-5p, hsa-miR-155-5p, hsa-miR-192-5p, and hsa-miR-199a-5p-expression levels as a panel of biomarkers for HCC in chronic hepatitis C virus (CHCV) patients with liver cirrhosis (LC), especially AFP-negative HCC cases, as a step toward non-protein coding (nc) RNA precision medicine. SUBJECTS AND METHODS: 79 patients enrolled with CHCV infection with LC, subclassified into an LC group without HCC (n = 40) and LC with HCC (n = 39). Real-time quantitative PCR was used to measure plasma hsa-miR-21-5p, hsa-miR-155-5p, hsa-miR-192-5p, and hsa-miR-199a-5p. RESULTS: Plasma hsa-miR-21-5p and hsa-miR-155-5p demonstrated significant upregulation, while hsa-miR-199a-5p demonstrated significant downregulation in the HCC group (n = 39) when compared to the LC group (n = 40). hsa-miR-21-5p expression was positively correlated with serum AFP, insulin, and insulin resistance (r = 0.5, p < 0.001, r = 0.334, p = 0.01, and r = 0.303, p = 0.02, respectively). According to the ROC curves, for differentiating HCC from LC, combining AFP with each of hsa-miR-21-5p, hsa-miR-155-5p, and miR199a-5p improved the diagnostic sensitivity to 87%, 82%, and 84%, respectively, vs. 69% for AFP alone, with acceptable specificities of 77.5%, 77.5%, and 80%, respectively, and AUC = 0.89, 0.85, and 0.90, respectively vs. 0.85 for AFP alone. hsa-miR-21-5p/hsa-miR-199a-5p and hsa-miR-155-5p/hsa-miR-199a-5p ratios discriminated HCC from LC at AUC = 0.76 and 0.71, respectively, with sensitivities = 94% and 92% and specificities = 48% and 53%, respectively. Upregulation of plasma hsa-miR-21-5p was considered as an independent risk factor for HCC development [OR = 1.198(1.063-1.329), p = 0.002]. CONCLUSIONS: Combining each of hsa-miR-21-5p, hsa-miR-155-5p, and hsa-miR-199a-5p with AFP made it possible to identify HCC development in the LC patients' cohort with higher sensitivity than using AFP alone. hsa-miR-21-5p/hsa-miR-199a-5p and hsa-miR-155-5p/hsa-miR-199a-5p ratios are potential HCC molecular markers for AFP-negative HCC patients. hsa-miR-21-5p was linked, clinically and via in silico proof, to insulin metabolism, inflammation, dyslipidemia, and tumorigenesis in the HCC patients' group as well as for an upregulated independent risk factor for the emergence of HCC from LC in the CHCV patients.