Study Time Points Research Articles

147-OR: Long-Term Effect of GLP-1 on Pancreas Endocrine Function after Gastric Bypass in Individuals with and without Diabetes Remission

The contribution of GLP-1 on glucose control after gastric bypass (GBP) is not fully elucidated. Hypotheses: The improvement in β-cell glucose sensitivity (BCGS) to oral glucose after GBP is GLP-1 mediated, weight loss independent, and varies according to diabetes (T2D) remission status; The administration of exendin 9-39 (EX9), a GLP-1 receptor blocker, has minimal effect on blood glucose. Methods: Patients with T2D (n=29) underwent a 75 g OGTT prior to and at 3, 12 and 24 months (M) after GBP. Glucose, insulin secretion rates (ISR), BCGS, and glucagon were measured with and without EX9. The cohort was retrospectively divided into 3 groups based on T2D remission status determined at the latest study time point (24 or 12M): remitters (REM, n=5), persistent T2D (P-T2D, n=8), impaired (IGT, n=16). Results: Prior to GBP, patients were 42.9±8.3y old, had a BMI of 42.4±4.6 kg/m2, 7.7±7.3 y known T2D duration, an HbA1c of 7.8±1.1% (35% on insulin) and an HOMA-IR of 11.5±5.8. Both magnitude and temporal increases in BCGS varied according to remission status: greater (up to 6.5 fold, p<0.03) and sustained in REM, variable in IGT (∼3 fold, p<0.01), minimal and only transient (3M, p=0.014) in P-T2D. These differences were not explained by weight-loss since it did not differ between the 3 groups at any time. EX9 reversed the effect of GBP on ISR at 3, 12 and 24M (p<0.003); it further enhanced the rise in post-prandial glucagon, but this effect was only significant at 3M (p=0.005). Both effects varied in magnitude overtime and by remission status. Glucose improved after GBP, as expected; EX9 decreased glucose levels at 3M in the whole cohort (p<0.001), but had no effect on glucose at 12 and 24M. EX9 increased significantly, albeit minimally, glucose at 120 and/or 180 minutes during the OGTT in REM and IGT, but not in P-T2D. Conclusions: Our data suggest that the effect of endogenous GLP-1 on pancreatic endocrine function and glucose varies with time and according to remission status after GBP. Disclosure M.A. Prasad: None. A. Shah: None. V.M. Mark: None. N. Nair: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. Funding National Institutes of Health (R01DK67561, DK007559, P30DK26687, UL1RR024156, UL1TR000040, F32DK113747)

277-OR: Teplizumab Reverses the Loss of C-Peptide in Relatives at Risk for Type 1 Diabetes (T1D)

We demonstrated that a 2-week course of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) delayed T1D progression by a median of 24 months in high risk relatives of patients with T1D (76 multiple islet autoantibody positive dysglycemic relatives; 912 day median follow-up). Over the study 72% of the placebo-treated and 43% of the teplizumab-treated participants were diagnosed with T1D. We hypothesized that teplizumab treatment would also result in a secondary outcome of improved C-peptide responses to oral glucose tolerance tests (OGTT) compared to placebo. The C-peptide, 1 hr insulin secretory rate (early ISR), and glucose area under the curve (AUC) means were calculated for each study timepoint. Results were modeled using ANCOVA, regressing on treatment group, age and the baseline value of the dependent variable. Teplizumab treatment was associated with a greater on-study C-peptide AUC (teplizumab vs. placebo adjusted means: 1.94 vs. 1.73 nmol/L; p=0.009). For both groups, C-peptide AUC mean slopes over a mean of 7.9 months preceding study entry were similar and significantly less than zero (declining; p=0.03). In the placebo group, this decline continued over the 6 months after study entry. By contrast, the teplizumab-treated group showed an increased C-peptide AUC over this period (p=0.003 relative to study entry). Insulin secretion during the 1st hr of the OGTT also declined in participants treated with placebo, but increased in those treated with teplizumab at 6 months (p=0.007). Increases in C-peptide AUC were correlated with increases in partially exhausted KLRG1+TIGIT+ CD8+ T cells (r=0.403; p=0.018). Although rates of diabetes were reduced in teplizumab-treated participants, OGTTs showed persistent dysglycemia. In conclusion, we found declines in C-peptide responses to OGTTs in high risk individuals prior to study treatment that were abrogated in the 6 month period after immunomodulation with teplizumab. Disclosure E.K. Sims: None. B.N. Bundy: None. K.D. Stier: None. E. Serti: None. N. Lim: None. G.T. Nepom: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. K.C. Herold: Consultant; Self; Provention Bio, Inc. Funding National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF

Growth Through 24 Months of Age in Infants Receiving Formulas with or Without Added Bovine Milk Fat Globule Membrane (MFGM) or Human Milk Through the First Year of Life: An RCT

Abstract Objectives To evaluate growth through 24 months of age in infants receiving added bovine milk fat globule membrane (MFGM) in infant formula through 12 months of age. Concentration of MFGM from bovine milk fractions and incorporation in infant formula may better approximate the composition of complex milk lipids in human milk. Methods In the double-blind, randomized, controlled Chilean Infant Nutrition Trial (ChiNuT; NCT0262613), term infants whose mothers chose to initiate exclusive infant formula feeding before 4 months of age were randomized to receive: a standard cow's milk-based infant formula (SF, n = 174) or a similar formula with added whey protein-lipid concentrate (5 g/L; source of bovine MFGM) (bMFGM, n = 176). A reference group of infants exclusively receiving human milk (HM, n = 236) was also recruited. Growth through 24 months of age was the primary outcome. Length-for-age (LAZ), weight-for-age (WAZ) and body mass index (BMI)-for-age (BAZ) growth z-scores were analyzed by mixed-effects multiple linear regression models adjusted by sex, age (days), and maternal pregestational BMI (kg/m2). Results No significant group differences in sex, gestational age at birth, birthweight, maternal age and maternal education were detected, with the exception of maternal pregestational BMI (mean(SD)) (HM: 27.0(5.2) lower vs SF: 28.6(6.2) or bMFGM: 28.9(6.1); P = 0.002). Groups were similar at baseline (weight, length, WAZ, BAZ) with the exception of LAZ (lower in the bMFGM compared to HM group; P < 0.05). No significant differences in growth z-scores (absolute at 6, 9, 12, and 24 months of age or change between baseline and each study time point) were detected between SF and MFGM groups. Both randomized study formula groups were associated with higher growth z-score increases from baseline compared to the HM reference group between 6 and 24 months (P less than 0.05). Mean growth z-scores fell within the range of −1 to 1 (16th to 84th percentile) for SF, bMFGM, and HM groups at all study time points. Conclusions Added bovine MFGM in a routine cow's milk-based infant formula through 12 months of age supported normal growth through 24 months of age. Funding Sources The study was funded by Mead Johnson Nutrition (MJN). Teresa Murguia-Peniche, Steven Wu, and Jennifer Wampler are currently employed by MJN. Carol Lynn Berseth was previously employed by MJN.

Assessing Early Behavioral Indicators of Tolerance in Infants Receiving Formula with Added Lactobacillus rhamnosus GG (LGG)

Abstract Objectives To evaluate the nutritive effects of an infant formula with added LGG on early behavioral indicators of tolerance in infants experiencing crying and fussing often associated with infantile colic. Methods In this single-center, double-blind, controlled, parallel, prospective study, infants (14 to 28 days of age) determined to cry and/or fuss ≥3 hours/day for ≥3 days/week (in a one-week period) were randomized to receive one of two formulas over a 21-day feeding period: marketed partially hydrolyzed (PH) cow's milk-based infant formula (PH: n, 35) or a similar formula with added LGG (PH-LGG: n, 36). Parents/caregivers used a validated parent-report diary to record crying/fussing and awake/content behavior at three time points: Study Days 2–4 (baseline), Days 10–12, and Days 18–20 (Study End). The primary outcome, duration (hours/day) of crying/fussing (averaged over each three-day period), was analyzed by repeated measures, mixed-effects models. Results Birth characteristics (sex, race, weight) and age (days; mean ± SE) at study entry (PH: 19.7 ± 0.8; PH-LGG: 19.3 ± 0.8) were similar for study groups. No group differences in mean study formula intake (g/day) or mean achieved weight (g) at any study time point were detected. Completion rates were similar through Day 21 (PH: n = 33, 94%; PH-LGG: n = 33, 92%). Duration of crying/fussing (mean ± SE) decreased over time with no significant differences detected in the PH vs PH-LGG group at Baseline (4.8 ± 0.3 vs 4.0 ± 0.3; P = 0.086), Days 10–12 (3.5 ± 0.3 vs 2.6 ± 0.3; P = 0.056), and Days 18–20 (2.1 ± 0.3 vs 1.5 ± 0.3; P = 0.227). Duration of awake/content behavior increased over time with no significant differences detected in PH vs PH-LGG: Baseline (1.0 ± 0.5 vs 1.2 ± 0.5; P = 0.786), Days 10–12 (1.3 ± 0.5 vs 1.6 ± 0.5; P = 0.627), and Days 18–20 (2.1 ± 0.5 vs 2.2 ± 0.5; P = 0.884). By Study End, only 8 (24%) in the PH and 9 (27%) in the PH-LGG group continued to cry and/or fuss ≥3 hours/day for ≥3 days/week. Conclusions In the present pilot study, we identified a study population of infants early in life experiencing crying and fussing often associated with infantile colic. Both study formulas were well tolerated. Crying/fussiness decreased and awake/content behavior increased in both study groups over the course of the study. Funding Sources Mead Johnson Nutrition.

Assessing Early Indicators of Tolerance and Stool Microbiome in Infants Receiving Formula with Added Lactobacillus rhamnosus GG (LGG)

Abstract Objectives To evaluate stool microbiome and calprotectin in infants receiving partially hydrolyzed protein formula with or without Lactobacillus rhamnosus GG (LGG). Methods In this single-center, double-blind, controlled, parallel, prospective study, infants (14-28 days of age) experiencing crying/fussing often associated with infantile colic were randomized to receive one of two formulas over a 21-day feeding period: marketed partially hydrolyzed (PH) cow's milk-based infant formula (PH: n, 35) or a similar formula with added LGG (PH-LGG: n, 36). Stool samples were collected at Baseline and Study End (Days 19–21). Stool calprotectin (μg/g) was determined by immunoassay and analyzed (Kruskal-Wallis). LGG colonization was determined by qPCR analysis.16S rRNA gene sequencing was performed (Illumina MiSeq) and QIIME operational taxonomic units (OTUs) were assigned (Greengenes database). Alpha and beta diversity were analyzed by study group and time point. Results A significantly higher abundance of LGG was demonstrated at Study End vs Baseline for the PH-LGG (P < 0.001) but not PH group (P = 0.89). Alpha diversity (Shannon) was significantly higher at Study End vs Baseline in the PH group (P = 0.014). By Study End, members of Phylum Firmicutes were significantly higher (P = 0.002) and Family Enterococcaceae were significantly lower (P = 0.02) in the PH-LGG group. No group differences in stool calprotectin (median) were detected at Baseline (PH: 12.4, n = 26; PH-LGG: 13.9, n = 30) or Study End (PH: 12.4, n = 30; PH-LGG: 12.9, n = 30). Conclusions In infants receiving a partially hydrolyzed protein formula with added LGG over a 21-day feeding period, LGG was established in the stool microbiome. Associated potentially beneficial bacterial taxa were also increased. Funding Sources Mead Johnson Nutrition.

Increased Physical Activity During Early Life Exacerbates High Fat Diet-Induced Bone Loss in Adult Mice

Abstract Objectives It has been recognized that mechanical stresses associated with physical activity (PA) have beneficial effects on increasing bone mineral density (BMD) and improving bone quality in humans and animal models. On the other hand, in rodents, high fat diet (HFD) and obesity increase bone marrow adiposity leading to increased production of pro-inflammatory cytokines that activate RANKL-induced bone resorption. In the current study, we investigated whether short-term increased PA via access to voluntary wheel running during early life has persistent effects on HFD-induced bone resorption. Methods Sixty (60) four-week-old male C57BL6/J mice were divided into two groups; without or with PA, access to voluntary running wheel (7 to 8 km per day) for 4 wks, with ad libitum access to control diet for all animals. After 4 wks with or without PA, mice were further subdivided into control diet or HFD groups for 8 wks, before all animals were switched back to control diet for an additional 4 wks. Mice from the HFD groups were significantly heavier, with more adiposity vs. control group at the 12 wk study time point, and returned to levels of mice with continues control diet at the 16 wk study time point. Results Using peripheral quantitative CT (pQCT) and micro-CT scan on tibias ex vivo, we determined that trabecular BMD and bone volume were significantly increased in animals after 4 wks of PA and control diet compared to sedentary animals without access to wheels. Eight weeks of HFD deteriorated bone development in mice, micro-CT showed 9% significant reduction on percentage of bone volume, and pQCT analysis showed 6% significant reduction of trabecular bone density of mice compared with those standard diet mice. Unexpectedly, early life PA exacerbated HFD-induced trabecular bone loss in adult mice. Early life PA accelerated HFD-induced osteoclastogenesis in adult mice. In accordance with these data, signal transduction studies revealed that HFD-induced Ezh2 and NFATc1, and IRF8 expression were amplified in non-adherent hematopoietic cells. Conclusions Increased PA in early life is capable of increasing bone mass; however, it alters the HFD-induced bone marrow hematopoietic cell differentiation program to exacerbate bone resorption if PA is halted. Funding Sources Supported in part by USDA-ARS Project 6026–51,000-010–05S.

Effects of an e-home based symptom management and mindfulness training program on quality of life in breast cancer survivors.

TPS12130 Background: The first five years post-treatment for breast cancer are a critical phase, when the survivors may face a multitude of problems, including persistent and/or late-emerging symptoms following the cancer and its treatment, psycho-social distress associated with the risk of cancer recurrence, chronic uncertainty and social disruption. Thus, this trial will answer the research questions of 'Will the combined symptom management and mindfulness-based training programme be a promising approach to assist women with breast cancer in transition from treatment to survivorship?', and 'Since breast cancer survivors have infrequent clinical follow-up, will e-Home based system provide a feasible option for post-treatment care?' Methods: We aim to develop an e-Home based symptom management and mindfulness training programme for breast cancer survivors and to determine its effects on the endpoints including quality of life, symptom distress, psychosocial adjustment, psychological morbidity, and unplanned outpatient attendance or hospitalisation in breast cancer survivors. (ClinicalTrials.gov Identifier: NCT02931864) We employ a randomised clinical trial with four study arms (with 47 subjects, who have completed cancer treatment for stage 0 to 3 breast cancer between 6 months to 5 years previously, in each arm) together with a process evaluation; group 1 (usual care), group 2 (experimental group: five weekly sessions of online symptom management + mindfulness training programme and usual care), group 3 (comparison group 1: online symptom management programme and usual care), and group 4 (comparison group 2: online mindfulness training programme and usual care). Subjects will complete questionnaires measures of 6-item Social Support Questionnaire, Breast Cancer Survivor Self- Efficacy Scale, the Quality of Life-Cancer Survivor Scale, Memorial Symptom Assessment Scale, Psychosocial Adjustment to Illness Scale, short version of the Fear of Recurrence Scale, Hospital and anxiety Depression Scale, and Five Facet Mindfulness Questionnaire at baseline, at 8 weeks from time 1 (time 2), at 12 weeks from time 1 (time 3) and at 24 weeks from time 1 (time 4). Intention-to-treat approach will be used. Repeated measures analysis of variance will be used to examine the differences on outcome measures among the experimental, comparison, and control groups across study time points. Currently, 162 of 188 planned subjects have been enrolled and the trial continues as planned. Clinical trial information: NCT02931864 .

Comparison of anti-capsular antibody quantity and functionality in children after different primary dose and booster schedules of 13 valent-pneumococcal conjugate vaccine

Different schedules for pediatric use of the 13-valent pneumococcal conjugate vaccine (PCV-13) are recommended in different countries and the U.S. Advisory Committee on Immunization Practices (ACIP) has considered potential of changing from 3 primary doses plus a booster (3p + 1) to two primary doses plus a booster (2p + 1) for protection against Streptococcus pneumoniae. In this paper, we report results of IgG antibody measured by ELISA and opsonophagocytic assay (OPA) after 2p, 3p, at child age 15 months of pre-booster and 18 months (post-booster) in serum samples opportunistically available from a prior study that focused on PCV effectiveness against AOM. A total of ~ 100 sera for each of the 4 study time points (390 sera tested) from 169 children were tested. Geometric mean concentrations (GMCs) and percentage of children exceeding the presumed protective antibody thresholds measured by ELISA and OPA were calculated. 2p doses produced lower antibody levels measured by ELISA but not OPA until the booster dose for serotypes 6A, 6B, 5 and 23F only. Booster dosing at 15 months resulted in significant increases in antibody. There was no difference in the percentage of children with ≥ correlate of protection (COP) for OPA for 2p vs 3p doses except for serotype 23F. A 2p + 0 or 3p + 0 schedule would likely result in many children failing to sustain protective levels of antibody into the second year of life. We conclude that protection from invasive pneumococcal infection in early childhood would be similar for most serotypes in PCV13 using a 2p + 1 or 3p + 1 but not a 2p + 0 or 3p + 0 schedule.

OR08-02 Do OGTT-based Insulin Secretory Response Measures Approximate 1st Phase Insulin Response in Pregnant Women?

Background: We previously showed that 1st phase insulin response increases dramatically in pregnancy, independent of changes in insulin sensitivity. Measurement of 1st phase insulin response requires the use of hyperglycemic clamps or intravenous glucose tolerance tests (IVGTTs) which are rarely performed in pregnant women. Oral glucose tolerance test (OGTT)-based measures of insulin secretory response have not been validated in pregnancy. Methods: In a secondary analysis of a longitudinal study of glucose metabolism in pregnancy, we examined Pearson correlations between OGTT-based insulin secretory response measures and 1st phase insulin response. Forty women were studied pre-pregnancy; 36 returned in early and late pregnancy (12–14 and 34–36 weeks gestation). At each time point, after overnight fasts, an IVGTT and an OGTT were performed on separate days. The 1st phase insulin response was calculated as the incremental area under the curve during the 1st 10 minutes after intravenous administration of a 0.5 g/kg glucose load (or 19g/m2 body surface area if weight >120% ideal body weight). Homeostatic Model Assessment (HOMAB), Insulinogenic index (IGI), Corrected insulin response (CIR), Insulin area under the curve/Glucose area under the curve (AUCins/AUCglu), and the Stumvoll 1st Phase Estimate (Stumvoll) were calculated from insulin and glucose levels measured fasting and 30, 60, 90, 120, and 180 minutes after an oral glucose load (75 grams pre-pregnancy, 100 grams in pregnancy). Results: The best OGTT-based measure for estimation of 1st phase insulin response differed across study timepoints. In early and late pregnancy, AUCins/AUCglu had the strongest correlation with 1st phase insulin response (early: R=0.79, P<0.0001; late: R=0.69, P<0.0001), but was not associated with 1st phase insulin response pre-pregnancy (R=0.32, P=0.08). IGI had the strongest correlation with first phase insulin response pre-pregnancy (R=0.50, P=0.005) and was correlated with 1st phase insulin response in late (R=0.68, P=0.0001), but not early (R=0.36, P=0.07) pregnancy. Stumvoll was the only OGTT-based measure that was significantly correlated with 1st phase insulin response at all timepoints (pre: R=0.44, P=0.01; early: R=0.67, P=0.0001; late: R=0.67, P=0.0001). HOMAB was the weakest correlate of 1st phase insulin response, though the correlation was significant in early pregnancy (pre: R=-0.04, P=0.82; early: R=0.33, P=0.05; late: R=0.18, P=0.28). Conclusion: OGTT-based measures of insulin secretion do not have a consistent relationship with 1st phase insulin response across pre-, early, and late pregnancy. Our findings suggest that Stumvoll can be used in OGTT-based longitudinal studies of insulin secretory response that begin prior to pregnancy and span gestation. For cross-sectional studies in pregnancy, AUCins/AUCglu are the best estimates of 1st phase insulin response.

Increased Oxidative Stress in Injured and Ill Elite International Olympic Rowers.

Identifying strategies that reduce the risk of illness and injury is an objective of sports science and medicine teams. No studies have examined the relationship between oxidative stress (OS) and illness or injury in international athletes undergoing periods of intensified training and competition. The authors aimed to identify relationships between illness, injury, and OS. A longitudinal, observational study of elite male rowers (n = 10) was conducted over 18 weeks, leading into World Championships. Following a recovery day and a 12-hour fast, hydroperoxides (free oxygen radicals test) and total antioxidant capacity (free oxygen radicals defense) were measured in venous blood, with the ratio calculated as the oxidative stress index (OSI). At all study time points, athletes were independently dichotomized as ill or not ill, injured or not injured. OS data were compared between groups using independent t tests. A Cox proportional hazard model was used to assess the association of OS with injury and illness while adjusting for age and body mass index. Free oxygen radicals defense was lower (P < .02) and OSI was higher (P < .001) with illness than without illness. Free oxygen radicals test and OSI were higher with injury than without injury (P < .001). A 0.5mmol·L-1 increase in free oxygen radicals defense was associated with a 30.6% illness risk reduction (95% confidence interval, 7%-48%, P = .014), whereas 0.5 unit increase in OSI was related to a 11.3% increased illness risk (95% confidence interval, 1%-23%, P = .036). OS is increased in injured and ill athletes. Monitoring OS may be advantageous in assessing recovery from and in reducing injury and illness risk given the association.

PRS2 PROPORTION OF PATIENTS WITH NASAL POLYPOSIS ACHIEVING CLINICALLY IMPORTANT IMPROVEMENTS IN QUALITY OF LIFE WITH OMALIZUMAB TREATMENT

Nasal polyps are associated with substantial quality of life (QoL) impairment. The 22-item sinonasal outcome test (SNOT-22) questionnaire is a widely accepted measure to evaluate the impact of chronic rhinosinusitis with nasal polyps (CRSwNP) on QoL over 4 symptom domains (nasal, otological, sleep, psychological). We examined QoL improvements using SNOT-22 total score (0–110; higher scores=greater impairment) in CRSwNP patients receiving omalizumab vs placebo in two replicate phase III, randomized, placebo-controlled, omalizumab studies, POLYP 1 and POLYP 2. Post-hoc analyses of data from POLYP 1 (n=138) and POLYP 2 (n=127) were performed. The proportion of patients achieving the minimal clinically important difference (MCID) of ≥8.9 point improvement, and adjusted mean change from baseline (95% CI) difference on SNOT-22 total score at Weeks 4, 8, 16 and 24 in omalizumab vs placebo groups are presented for the pooled POLYP 1/2 population. Safety results have been presented previously (Gevaert P, Ann Allergy Asthma Immunol 2019;123[5]:S17). Baseline mean (SD) SNOT-22 total scores were similar for omalizumab- and placebo-treated patients (59.5 [20.0]; N=134 vs 60.1 [16.7]; N=131, respectively). At each study time point, the MCID in SNOT-22 total score was achieved with omalizumab, and SNOT-22 total score improvements were greater vs placebo (adjusted mean differences [95% CI]: -9.38 [-12.78, -5.99], -13.18 [-16.99, -9.38], -15.71 [-19.67, -11.74], and -15.36 [-19.57, -11.16] at Weeks 4, 8, 16, and 24, respectively). Omalizumab-treated patients were more likely than placebo-treated patients to achieve MCID in SNOT-22 at Weeks 4 (66.7% vs 45.7%; OR=2.42; [95% CI: 1.46, 4.01]), 8 (78.2% vs 48.8%; OR=3.91; [2.27, 6.76]), 16 (79.2% vs 45.0%; OR=4.91 [2.81, 8.60]), and 24 (73.4% vs 43.8%; OR=3.66 [2.15, 6.23]). Omalizumab treatment resulted in placebo-corrected mean SNOT-22 clinically meaningful differences, with a substantially higher proportion of omalizumab-treated patients achieving a clinically important improvement in QoL.

PDB111 A COMPARATIVE EFFECTIVENESS RESEARCH STUDY OF A NATIVE TYPE I COLLAGEN MATRIX PLUS POLYHEXAMETHYLENE BIGUANIDE ANTIMICROBIAL AND A CRYOPRESERVED CADAVERIC SKIN ALLOGRAFT FOR USE IN DIABETIC FOOT ULCERS - A NON-INFERIORITY ANALYSIS

Real-world effectiveness was evaluated in a large patient population at 189 US treatment facilities comparing a purified native cross-linked extracellular matrix plus polyhexamethylene biguanide antimicrobial barrier (PCMP) and a cryopreserved cadaveric skin allograft (CCSA) for use in diabetic foot ulcers (DFUs). Electronic medical records were the source of these retrospective data. Treatment records collected from 2011-2019 on 945 patients (1,032 DFUs) were analyzed. Exclusion criteria were lack of baseline wound measurements or follow-up visits. Evaluations were performed on 314 PCMP patients (349 DFUs), and 631 CCSA patients (683 DFUs). Treatment cohorts were well matched. Baseline, mean areas were 6.2 and 7.8 cm2, mean depths were 4.0 and 3.5 mm, and median durations were 9.3 and 7.0 months, for PCMP and CCSA respectively. The median number of treatment applications was 2.0 in both groups, and the mean interval between treatment applications was 14.4 vs 24.1 days for PCMP and CCSA respectively. A Cox proportional hazards regression analysis (Cox) that adjusted for ulcer size, depth, and duration was used to compute frequency and probability of wound closure. The PCMP vs CCSA frequencies of wound closure were comparable at all study timepoints including week 4 (11 vs 10%), 8 (25 vs 24%), and 12 (36 vs 37%) respectively (p=0.20). PCMP demonstrated a comparable probability of wound healing vs CCSA treatment (Hazard Ratio=0.89 [95% CI: 0.75, 1.06]; p=0.20). In a Non-Inferiority (NI) analysis, PCMB demonstrated equivalence to CCSA when tested at a clinical margin of 20% (p=0.03). These real-world data demonstrate that PCMP vs CCSA showed comparable wound closure outcomes when used in DFUs. The NI design allows a valid conclusion of statistically significant equivalence between PCMP and CCSA at the clinical margin tested. These findings may inform wound care treatment algorithms and have meaningful clinical and health care economic implications.

Dysregulated activities of proline-specific enzymes in septic shock patients (sepsis-2).

The proline-specific enzymes dipeptidyl peptidase 4 (DPP4), prolylcarboxypeptidase (PRCP), fibroblast activation protein α (FAP) and prolyl oligopeptidase (PREP) are known for their involvement in the immune system and blood pressure regulation. Only very limited information is currently available on their enzymatic activity and possible involvement in patients with sepsis and septic-shock. The activity of the enzymes was measured in EDTA-plasma of patients admitted to the intensive care unit (ICU): 40 septic shock patients (sepsis-2) and 22 ICU control patients after major intracranial surgery. These data were used to generate receiver operating characteristic (ROC) curves. A survival analysis (at 90 days) and an association study with other parameters was performed. PRCP (day 1) and PREP (all days) enzymatic activities were higher in septic shock patients compared to controls. In contrast, FAP and DPP4 were lower in these patients on all studied time points. Since large differences were found, ROC curves were generated and these yielded area under the curve (AUC) values for PREP, FAP and DPP4 of 0.88 (CI: 0.80-0.96), 0.94 (CI: 0.89-0.99) and 0.86 (CI: 0.77-0.95), respectively. PRCP had a lower predicting value with an AUC of 0.71 (CI: 0.58-0.83). A nominally significant association was observed between survival and the DPP4 enzymatic activity at day 1 (p<0.05), with a higher DPP4 activity being associated with an increase in survival. All four enzymes were dysregulated in septic shock patients. DPP4, FAP and PREP are good in discriminating between septic shock patients and ICU controls and should be further explored to see whether they are already dysregulated in earlier stages, opening perspectives for their further investigation as biomarkers in sepsis. DPP4 also shows potential as a prognostic biomarker. Additionally, the associations found warrant further research.

Safety and immunogenicity of a modified vaccinia virus Ankara vector vaccine candidate for Middle East respiratory syndrome: an open-label, phase 1 trial

BackgroundThe Middle East respiratory syndrome coronavirus (MERS-CoV) causes a respiratory disease with a case fatality rate of up to 35%. Given its potential to cause a public health emergency and the absence of efficacious drugs or vaccines, MERS is one of the WHO priority diseases warranting urgent research and development of countermeasures. We aimed to assess safety and tolerability of an anti-MERS-CoV modified vaccinia virus Ankara (MVA)-based vaccine candidate that expresses the MERS-CoV spike glycoprotein, MVA-MERS-S, in healthy adults.MethodsThis open-label, phase 1 trial was done at the University Medical Center Hamburg-Eppendorf (Hamburg, Germany). Participants were healthy men and women aged 18–55 years with no clinically significant health problems as determined during medical history and physical examination, a body-mass index of 18·5–30·0 kg/m2 and weight of more than 50 kg at screening, and a negative pregnancy test for women. A key exclusion criterion was a previous MVA vaccination. For the prime immunisation, participants received doses of 1 × 107 plaque-forming unit (PFU; low-dose group) or 1 × 108 PFU (high-dose group) MVA-MERS-S intramuscularly. A second identical dose was administered intramuscularly as a booster immunisation 28 days after first injection. As a control group for immunogenicity analyses, blood samples were drawn at identical study timepoints from six healthy adults, who did not receive any injections. The primary objectives of the study were safety and tolerability of the two dosage levels and reactogenicity after administration. Immunogenicity was assessed as a secondary endpoint by ELISA and neutralisation tests. T-cell immunity was evaluated by interferon-γ-linked enzyme-linked immune absorbent spot assay. All participants who were vaccinated at least once were included in the safety analysis. Immunogenicity was analysed in the participants who completed 6 months of follow-up. This trial is registered with ClinicalTrials.gov, NCT03615911, and EudraCT, 2014-003195-23FindingsFrom Dec 17, 2017, to June 5, 2018, 26 participants (14 in the low-dose group and 12 in the high-dose group) were enrolled and received the first dose of the vaccine according to their group allocation. Of these, 23 participants (12 in the low-dose group and 11 in the high-dose group) received a second dose of MVA-MERS-S according to their group allocation after a 28-day interval and completed follow-up. Homologous prime–boost immunisation with MVA-MERS-S revealed a benign safety profile with only transient mild-to-moderate reactogenicity. Participants had no severe or serious adverse events. 67 vaccine-related adverse events were reported in ten (71%) of 14 participants in the low-dose group, and 111 were reported in ten (83%) of 12 participants in the high-dose group. Solicited local reactions were the most common adverse events: pain was observed in 17 (65%; seven in the low-dose group vs ten in the high-dose group) participants, swelling in ten (38%; two vs eight) participants, and induration in ten (38%; one vs nine) participants. Headaches (observed in seven participants in the low-dose group vs nine in the high-dose group) and fatigue or malaise (ten vs seven participants) were the most common solicited systemic adverse events. All adverse events resolved swiftly (within 1–3 days) and without sequelae. Following booster immunisation, nine (75%) of 12 participants in the low-dose group and 11 (100%) participants in the high-dose group showed seroconversion using a MERS-CoV S1 ELISA at any timepoint during the study. Binding antibody titres correlated with MERS-CoV-specific neutralising antibodies (Spearman's correlation r=0·86 [95% CI 0·6960–0·9427], p=0·0001). MERS-CoV spike-specific T-cell responses were detected in ten (83%) of 12 immunised participants in the low-dose group and ten (91%) of 11 immunised participants in the high-dose group.InterpretationVaccination with MVA-MERS-S had a favourable safety profile without serious or severe adverse events. Homologous prime–boost immunisation induced humoral and cell-mediated responses against MERS-CoV. A dose–effect relationship was demonstrated for reactogenicity, but not for vaccine-induced immune responses. The data presented here support further clinical testing of MVA-MERS-S in larger cohorts to advance MERS vaccine development.FundingGerman Center for Infection Research.

The Effect of Orthognathic Surgery on Soft-Tissue Facial Asymmetry: A Longitudinal Three-Dimensional Analysis.

In modern orthognathic surgery, the functional results cannot disregard a good aesthetic outcome. In this study, a stereophotogrammetric longitudinal analysis of the symmetry of facial thirds was performed in 18 patients affected by Class III skeletal malocclusion, with clinical asymmetry, treated with a bimaxillary osteotomy. Their 3-dimensional facial images were acquired in the preoperative phase and 6, 12, and 24 months after surgery, and compared to those obtained in a control group of 23 subjects with Class I skeletal occlusion, without clinical asymmetry and no history of traumas or alterations at the maxillo-facial area. Images of the hemi-faces of the subjects were divided into thirds (upper, middle, lower), mirrored and superimposed to their contralateral ones; soft-tissue facial symmetry was obtained as the root mean square distance between the hemi-faces in the three thirds.In patients, no significant differences in facial symmetry (root mean square distance) were found among the study time points (analysis of variance, P > 0.05); the lower facial third was more asymmetric than the upper one (Tukey honestly significant difference P < 0.05). Patients were significantly more asymmetric than the control subjects (Student t, P < 0.05). In conclusion, patients with Class III malocclusion exhibited a higher level of facial asymmetry than control subjects; their asymmetry did not change significantly in the different phases of the surgical and orthodontic treatment and throughout a 24-month follow-up. In skeletal Class III patients, bimaxillary osteotomy did not modify the level of asymmetry in any facial third.

Investigating the effects of Progressive Right Ventricular Remodeling on Systolic and Diastolic RV Function in a Longitudinal Animal Model Study of Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is a progressive vasculopathy which increases pulmonary vascular resistance and induces a pressure overload on the right ventricle, however the mechanisms by which the RV adapts to pressure overload is not well understood 1. The purpose of this study was to characterize the mechanistic progression of earlier‐stage right ventricular compensated remodeling in an animal model of PAH. In a longitudinal study of the Sugen‐Hypoxia animal model of PAH, invasive RV catherization measurements were used to assess right heart function, including RV pressure and volume relations, hemodynamic parameters, and systolic and diastolic elastance measures. Because RV ejection fraction has been found to be transiently maintained in early stage remodeling, this study also sought to distinguish the contributions of systolic and diastolic volume preservation or increases in stroke volume to this maintenance 2. To elucidate the mechanistic contributions to changes in organ‐level cardiac function over the course of PAH progression, a computational model was developed to differentiate between contributions due to RV geometric remodeling such as chamber dilatation and wall thickening from contributions due to intrinsic sarcomere changes such as myocardial contractility. Over the course of PAH progression, pulmonary vascular resistance and end systolic and end diastolic pressures continuously increased, while end systolic and diastolic volumes seemed to maintain. Ejection fraction and stroke volume also seemed to maintain over this period of compensated RV remodeling. Computational model analysis of RV myocardial wall mechanics and RV geometry seemed to indicate that changes in sarcomere mechanical properties were required to predict both end‐systolic and end‐diastolic PV relations throughout the study time points. Passive material parameters increased between early weeks 3–4 to mid weeks 5–6 to late weeks 8–10. Active material parameters indicated that large increases in myocardial inotropy, in part due to increases in intracellular calcium concentration and sarcomere length, occurred in order to maintain RV compensation after four weeks, and remained high through ten weeks. Ongoing biochemical analysis and tissue mechanical testing of the extracellular matrix indicate that significant contribution of fibrotic collagen deposition and stiffening of the ECM in the later weeks may explain increase in diastolic stiffness. Distinguishing between the specific mechanistic contributors to RV compensated remodeling can help identify the mediators of the transition between early stage compensated RV remodeling and later stage decompensated RV remodeling.Support or Funding InformationNational Institutes of Health NHLBI 1T32HL 105373

Nettle Agent Phosgene Oxime Toxicity and Related Mechanism from its Dermal Exposure

Phosgene Oxime (dichloroform oxime; CX), an urticant or nettle agent categorized as a vesicant, is a potential chemical threat agent. Its exposure causes rapid toxicity, severe pain with dermal symptoms including erythema (redness), urticaria, blanching, itching hives, necrosis and systemic effects. Due to its fast penetration, severe dermal injury, and instant lethal toxic effects resulting in high mortality, CX could be weaponized with other chemical threat agents to enhance their deleterious effects. Skin damage with erythema, necrosis and inflammation following cutaneous exposure to CX and vesicants, e.g. sulfur mustard (SM; mustard gas), nitrogen mustard (NM) and lewisite (L), is similar; however, CX also causes severe skin injury with immediate urticaria and blanching as well as mortality. The skin urticaria from CX resembles urticaria caused by allergic and non‐allergic reactions to various environmental substances and can occur alone or can be associated with lethal allergic reaction, anaphylaxis. CX is one of the least studied vesicating agent with no effective treatment available. In the present study, we exposed the dorsal skin of SKH‐1 hairless mice with neat CX for 0.5 and 1.0 min using two 12 mm vapor caps, and studied different parameters associated with its pathophysiology. Clinical data from our study showed that CX exposure leads to acute skin lesions (edema, erythema, necrosis, urticaria and blanching) as well as decreases in heart and respiratory rate, drop in body temperature, vasculature dilation and blood congestion in multiple organs indicating urticaria and anaphylaxis. Histopathological analysis showed a CX‐induced increase of over 2‐fold in the mouse skin epidermal thickness at 2 hr and 14 days following 0.5 min and 1.0 min exposures, respectively. Similarly, 1.5–2.0‐fold increase in dermal plus hypodermal thickening was observed at all study time points following 0.5 and 1.0 min CX exposures. Dermal fibrosis, necrotic blood vessels, hyperkeratosis, cell death and an increase in inflammatory cells was also observed at day 1 and 14 following 0.5 min CX exposure. Edema, necrosis and dying fat cells were observed within 2 hr in the skin of both the CX exposure groups. CX induced an increase in mast cell degranulation within 30 min of its exposure which peaked to over 90% at 24 hr post exposure and was associated with increased histamine and tryptase levels. In addition, an increase in the level of MMP9 and DNA damage maker (pH2AX) in skin tissues was also observed. The results from our completed studies suggest that mast cells could be important players in CX‐ and probably other vesicating agents‐induced toxicity. Hence, molecular markers and cytokines associated with CX‐induced mast cell degranulation as well as inflammatory and DNA damage responses are being evaluated to identify the signaling pathways and key molecular targets for further therapeutic approaches to counteract toxicity from CX cutaneous exposure in case of a chemical emergency.

The Effect of Conscious Sedation on Salivary Alpha-Amylase Levels During Third Molar Surgery

Aim: The aim of the present study was to investigate whether salivary alpha-amylase levels could be decreased by conscious sedation in the patients undergoing impacted third molar extraction. Material and methods: A total of 18 male patients were recruited. All patients were administered the Modified Dental Anxiety Scale test. Patients were divided into a test group (procedures under sedation) and a control group (procedures under local anesthesia). Systolic blood pressure, diastolic blood pressure, oxygen saturation, and heart rate were monitored at different study time-points. Five samples of saliva were taken from each patient: the first time the patient came to the clinic, the patient sat in the chair for extraction, before local anesthesia, immediately after extraction, at 4 h after extraction. Results: Although no statistically important difference was found for systolic blood pressure (p>0.05) between groups, postoperative diastolic blood pressure level of control group was statistically higher than the test group (p=0.030). Also, a statistically significant decrease was found in the oxygen saturation level in postoperative time compared to preoperative time (p<0.05). Conclusion: Even though conscious sedation may be a solution for dental anxiety and phobia, our results indicated that sedation did not affect acute stress levels during oral surgery.

One-Year Evaluation of a Targeted Medication Therapy Management Intervention for Older Adults.

Older adults are especially susceptible to adverse effects of inappropriate medication therapy, and anticholinergic medications are common culprits for cognitive dysfunction due to their action on the central nervous system. Medication therapy management (MTM) interventions can aid in deprescribing and reducing inappropriate medication use in older adults. However, there is sparse literature on the long-term sustainability of these interventions. To (a) investigate whether the deprescribing of anticholinergic medications during an 8-week randomized controlled trial (RCT) of a targeted MTM intervention is sustained at 1-year postintervention follow-up and (b) compare anticholinergic utilization trends in the study population with a large sample of similar individuals not exposed to the intervention. Participants in the targeted MTM (tMTM) RCT had normal cognition or mild cognitive impairment and were recruited from enrollees in a longitudinal study at the University of Kentucky Alzheimer's Disease Center (ADC) and thus have pertinent medical information gathered approximately annually. In this posttrial observational follow-up, sustainability of the anticholinergic deprescribing intervention was assessed in participants in the RCT, and anticholinergic medication use trends were described from the RCT baseline (which occurred immediately following an ADC visit) to the next annual visit in all participants. Mean change in anticholinergic burden from RCT baseline to the next annual visit was estimated using analysis of covariance, and participants were compared with 2 external samples. Anticholinergic burden was measured using the Anticholinergic Drug Scale (ADS). The odds of decreasing baseline anticholinergic burden and number of total and strong anticholinergic medications at the follow-up study time point was assessed using logistic regression. Of the deprescribing changes made during the initial RCT, 50% were sustained after 1 year. Participants in the tMTM trial reported decreases in the use of anticholinergic antihistamines and bladder agents (-6.5 and -4.4%, respectively), but there was no change in the use of anticholinergic agents targeted at the central nervous system. While the anticholinergic burden of RCT participants decreased over 1 year (adjusted mean ADS change [95% CI] = -0.33 [-0.72, 0.07]), it was not different than the change observed in 2 external samples at the trial center (-0.20 [-0.42, 0.02]) and nationally (-0.33 [-0.39, -0.26]). There were no statistically significant differences between trial participants and external samples in the odds of decreasing anticholinergic burden nor in decreasing the number of total, or strongly anticholinergic, medications at the 1-year follow-up. This study demonstrates that the sustainability of deprescribing is limited to the period of intervention, rather than affording lasting effects even over periods as short as 1 year, which was demonstrated not only in the small group of RCT participants but also by comparison with external groups. Future work should extend the duration of intervention and follow-up periods for MTM interventions to allow further insights regarding the sustainability of deprescribing efforts in older adults. The original trial was supported by a pilot study award from the University of Kentucky Center for Clinical and Translational Sciences (UL1TR000117). Additional support for this study was provided by the National Institutes of Health/National Institute on Aging (R01 AG054130). Jicha reports contract research for Esai, Biohaven, Alltech, Suven, Novartis, and Lilly. The other authors have nothing to disclose.

Immunosuppressant-Induced Oxidative Stress and Iron: A Paradigm Shift from Systemic to Intrahepatic Abnormalities.

Immunosuppressants are used clinically to lower rejection rates in transplant patients. Unfortunately, the adverse side effects of these immunosuppressants can be severe, which is one of the rationales that life expectancy of individuals after transplant still significantly falls short of that of the general population. The current experimental setup was designed to analyze the tacrolimus-induced hepatic iron overload in Wistar rats. Four experimental groups were orally given 1 ml of aqueous suspension of tacrolimus (12 mg/kg) through oral gavage, and rats were sacrificed after 6, 12, 24, and 48 h of tacrolimus dose. Hepatic hepcidin expression was found to be significantly augmented along with the upregulation of Tf and TfR1, Ferritin-L, Ferritin-H, TNF-α, and HO-1 gene expression at 6 and 12 h, and downregulation of Fpn-1, Hjv, and Heph at 6 h was detected. Significant downregulation of IL-6, IFN-α, IFN-β, and IFN-γ at all study time points was also observed. Serum iron level was decreased while serum hepcidin level was found to be significantly increased. Iron staining showed blue-stained hemosiderin granules within the hepatocytes, sinusoidal spaces, and portal areas at 12 and 24 h time points and remarkable fall of iron contents in the splenic red pulp. These results suggest that the use of tacrolimus leads to the onset of an intrahepatic acute-phase response-like reaction and causes iron overload in hepatic cells by altering the expression of key proteins involved in iron metabolism.