Efficacy and Predictors of Pain Response to Combined Antioxidants in Children with Chronic Pancreatitis.

BACKGROUND: Pain is a major problem in 90% of patients with chronic pancreatitis (CP). Studies evaluating response to antioxidants (AO) are conflicting and no pediatric studies are available. AIMS: To evaluate markers of oxidative stress (OS), and efficacy and predictors of response to AO in improving pain in children with CP. METHODS: Antioxidants were given to CP children for 6 months. Subjects were assessed at baseline and post-therapy for pain and markers of OS [serum thiobarbituric acid reactive substances (TBARS), superoxide dismutase (S-SOD)] and antioxidant levels [vitamin C, selenium, total antioxidant capacity-ferric reducing ability of plasma (FRAP)]. Matched healthy controls were assessed for OS and antioxidant levels. Good response was defined as ≥ 50% reduction in number of painful days/month. RESULTS: 48 CP children (25 boys, age 13 years) and 14 controls were enrolled. 38/48 cases completed 6 months of therapy. CP cases had higher OS [TBARS (7.8 vs 5.2 nmol/mL; p < 0.001)] and lower antioxidant levels [FRAP (231 vs. 381.3 µmol/L; p = 0.003), vitamin C (0.646 vs. 0.780 mg/dL; p < 0.001)] than controls. Significant reduction in TBARS and S-SOD and increase in FRAP, vitamin C, and selenium occurred after 6 months. 10.5% cases had minor side effects. 26(68%) cases had a good response, with 9(24%) becoming pain-free. Subjects with severe ductal changes had lower median BMI (- 0.73 vs 0.10; p = 0.04) and responded less often than those with mild changes (17/29 vs 9/9; p = 0.036). CONCLUSION: CP children have higher OS than healthy controls. Antioxidant therapy is safe. Pain response is seen in 68% cases, less often in patients with severe ductal changes.

Targeted inhibition of thrombin attenuates murine neonatal necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants and an orphan disease with no specific treatment. Most patients with confirmed NEC develop moderate-severe thrombocytopenia requiring one or more platelet transfusions. Here we used our neonatal murine model of NEC-related thrombocytopenia to investigate mechanisms of platelet depletion associated with this disease [K. Namachivayam, K. MohanKumar, L. Garg, B. A. Torres, A. Maheshwari, Pediatr. Res. 81, 817-824 (2017)]. In this model, enteral administration of immunogen trinitrobenzene sulfonate (TNBS) in 10-d-old mouse pups produces an acute necrotizing ileocolitis resembling human NEC within 24 h, and these mice developed thrombocytopenia at 12 to 15 h. We hypothesized that platelet activation and depletion occur during intestinal injury following exposure to bacterial products translocated across the damaged mucosa. Surprisingly, platelet activation began in our model 3 h after TNBS administration, antedating mucosal injury or endotoxinemia. Platelet activation was triggered by thrombin, which, in turn, was activated by tissue factor released from intestinal macrophages. Compared to adults, neonatal platelets showed enhanced sensitivity to thrombin due to higher expression of several downstream signaling mediators and the deficiency of endogenous thrombin antagonists. The expression of tissue factor in intestinal macrophages was also unique to the neonate. Targeted inhibition of thrombin by a nanomedicine-based approach was protective without increasing interstitial hemorrhages in the inflamed bowel or other organs. In support of these data, we detected increased circulating tissue factor and thrombin-antithrombin complexes in patients with NEC. Our findings show that platelet activation is an important pathophysiological event and a potential therapeutic target in NEC.

The Association between Prolonged Antibiotic Use in Culture Negative Infants and Length of Hospital Stay and Total Hospital Costs.

OBJECTIVE: This study aimed to determine if prolonged antibiotic use at birth in neonates with a negative blood culture increases the total cost of hospital stay. STUDY DESIGN: This was a retrospective study performed at a 60-bed level IV neonatal intensive care unit. Neonates born <30 weeks of gestation or <1,500 g between 2016 and 2018 who received antibiotics were included. A multivariate linear regression analysis was conducted to determine if clinical factors contributed to increased hospital cost or length of stay. RESULTS: In total, 190 patients met inclusion criteria with 94 infants in the prolonged antibiotic group and 96 in the control group. Prolonged antibiotic use was associated with an increase length of hospital stay of approximately 31.87 days, resulting in a $69,946 increase in total cost of hospitalization. CONCLUSION: Prolonged antibiotics in neonates with negative blood culture were associated with significantly longer hospital length of stay and increased total cost of hospitalization. KEY POINTS: · Prolonged antibiotic use at birth is associated with prolonged hospital stay.. · Prolonged antibiotic use at birth is associated with increased cost of hospitalization.. · Prolonged antibiotic use at birth is associated with increased days on total parenteral nutrition.. · Prolonged antibiotic use at birth is associated with increased subsequent courses of antibiotics..

Neurodevelopmental Outcomes of Preterm Infants Born <29 Weeks with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension: A Multicenter Study.

OBJECTIVE: This study aimed to determine neurodevelopmental outcomes of preterm infants born at <29 weeks' gestational age (GA) with bronchopulmonary dysplasia and pulmonary hypertension (BPD-PH) at 18 to 24 months' corrected age (CA). STUDY DESIGN: In this retrospective cohort study, preterm infants born at <29 weeks' GA between January 2016 and December 2019, admitted to level 3 neonatal intensive care units, who developed BPD and were evaluated at 18 to 24 months' CA in the neonatal follow-up clinics were included. We compared demographic characteristics and neurodevelopmental outcomes between the two groups: Group I: BPD with PH and Group II: BPD with no PH, using univariate and multivariate regression models. The primary outcome was a composite of death or neurodevelopmental impairment (NDI). NDI was defined as any Bayley-III score < 85 on one or more of the cognitive, motor, or language composite scores. RESULTS: Of 366 eligible infants, 116 (Group I [BPD-PH] =7, Group II [BPD with no PH] = 109) were lost to follow-up. Of the remaining 250 infants, 51 in Group I and 199 in Group II were followed at 18 to 24 months' CA. Group I and Group II had median (interquartile range [IQR]) birthweights of 705 (325) and 815 g (317; p = 0.003) and median GAs (IQR) were 25 (2) and 26 weeks (2; p = 0.015) respectively. Infants in the BPD-PH group (Group I) were more likely to have mortality or NDI (adjusted odds ratio: 3.82; bootstrap 95% confidence interval; 1.44-40.87). CONCLUSION: BPD-PH in infants born at <29 weeks' GA is associated with increased odds of the composite outcome of death or NDI at 18 to 24 months' CA. KEY POINTS: · Long-term neurodevelopmental follow-up of preterm infants born <29 weeks' GA.. · Association of neurodevelopmental outcomes with BPD-associated PH.. · Need for longitudinal follow-up of children with BPD-associated PH..

Prevalence and predictive factors of undernutrition and low bone mineral density in children with chronic pancreatitis.

BACKGROUND: Malnutrition and bone disease are common in adults with chronic pancreatitis (CP). We studied the nutritional status and bone mineral density (BMD) of children with CP and the factors predicting them. METHODS: CP children were prospectively evaluated with a detailed questionnaire, anthropometry, 25-hydroxy vitamin D, fecal elastase and BMD [total body less head (TBLH), spine and hip] by dual energy x-ray absorptiometry. Body mass index (BMI) Z score of -1 to -1.9, -2 to -2.9 and <-3 was taken as mild, moderate and severe malnutrition respectively. Low BMD and osteoporosis were defined as per International Society for Clinical Densitometry. RESULTS: 83 children (46 boys, 14[4.3-21]years) with CP were enrolled. Majority had Cambridge IV (51,62.2%) or III (15,18.3%) changes. 34(41%) had undernutrition (mild-37.3%, moderate-2.4%, severe-1.2%). Overweight and obesity were present in 3.6% and 1.2% cases. BMI had a significant correlation with haemoglobin, serum albumin, percentage body fat and BMD. A majority had low fecal elastase (69 [84.1%], <100 µg/g) and vitamin D deficiency (70[84.3%],<20 ng/ml). 9 cases had a history of fractures. 14/75(18.6%) cases had low TBLH-BMD and this group had a lower BMI (-1.3[-1.9 to 0.34] vs 0.8 [-2.1 to 5.50; p = 0.03) than patients with normal BMD. There was no difference in age, disease duration, vitamin D, fecal elastase and Cambridge grade between normal and low BMD. CONCLUSIONS: 41% CP children have undernutrition with a majority having mild undernutrition. Nearly 20% have low BMD, with osteoporosis in none. Subjects with low BMI have lower BMD and percentage body fat.

Lyophilization of human amniotic fluid is feasible without affecting biological activity.

BACKGROUND: Fetal swallowing of human amniotic fluid (hAF) containing trophic factors (TFs) promotes gastrointestinal tract (GIT) development. Preterm birth interrupts hAF swallowing, which may increase the risk of necrotizing enterocolitis (NEC). Postnatally, it is difficult to replicate fetal swallowing of hAF due to volume. We aimed to evaluate whether hAF lyophilization is feasible and its effect on hAF-borne TFs. METHODS: We collected hAF (n = 16) from uncomplicated pregnancies. hAF was divided into three groups: unprocessed control (C), concentration by microfiltration (F), and by dialysis and lyophilization (L). EGF, HGF, GM-CSF, and TGF-α were measured in each group by multiplex assay. Bioavailability of TFs was measured by proliferation and LPS-induced IL-8 production by intestinal epithelial cells FHs74. RESULTS: After dialysis/lyophilization, GM-CSF and TGF-α were preserved with partial loss of EGF and HGF. hAF increased cell proliferation and reduced LPS-induced IL-8 production compared to medium alone. Compared to control, dialysis/lyophilization and filtration of hAF increased FHs74 cell proliferation (p < 0.001) and decreased LPS-induced IL-8 production (p < 0.01). CONCLUSIONS: Lyophilization and filtration of hAF is feasible with partial loss of TFs but maintains and even improves bioavailability of TFs measured by proliferation and LPS-induced IL-8 production by FHs74.

Liraglutide as add-on to sodium-glucose co-transporter-2 inhibitors in patients with inadequately controlled type 2 diabetes: LIRA-ADD2SGLT2i, a 26-week, randomized, double-blind, placebo-controlled trial.

AIM: To compare the effect of liraglutide or placebo added on to sodium-glucose co-transporter-2 inhibitor (SGLT2i) ± metformin on glycaemic control in patients with type 2 diabetes. MATERIALS AND METHODS: Patients with type 2 diabetes on a stable SGLT2i dose ± metformin (with HbA1c 7.0%-9.5% and body mass index [BMI] ≥ 20 kg/m2 ) were randomized 2:1 to add-on liraglutide 1.8 mg/day or placebo in this parallel, double-blind, multinational trial. Primary and confirmatory secondary endpoints were changes in HbA1c and body weight from baseline to week 26, respectively. The proportions of patients achieving HbA1c (<7.0%) targets and safety events after week 26 were also assessed. RESULTS: Of 303 patients randomized (one in error), 280 completed treatment. Mean changes in HbA1c from baseline to week 26 with liraglutide (n = 202) and placebo (n = 100) were - 0.98% and - 0.30%, respectively (estimated treatment difference [ETD]: -0.68% [95% CI: -0.89, -0.48]; P < 0.001). Mean body weight changes from baseline were - 2.81 versus -1.99 kg, respectively (ETD: -0.82 kg [95% CI: -1.73, 0.09]; P = 0.077); 51.8% of liraglutide-treated patients achieved HbA1c < 7.0% versus 23.2% receiving placebo (odds ratio: 5.1 [95% CI: 2.67, 9.87]; P < 0.001). More patients treated with liraglutide reported ≥1 treatment-emergent adverse events (66.3%) versus placebo (47.0%). CONCLUSIONS: Liraglutide significantly improved glycaemic control compared with placebo in patients with type 2 diabetes, insufficiently controlled with SGLT2is with/without metformin, with no unexpected safety findings.

99mTc-labelled and pH-awakened microbeads entrapping surface-modified lipid nanoparticles for the augmented effect of oxaliplatin in the therapy of colorectal cancer.

AIM: This study was aimed to develop Eudragit S100-coated, pH-awakened microbeads (MBs) encapsulating folic acid (FA)-modified tristearin solid lipid nanoparticles (SLNs) loaded with oxaliplatin (OP). Afterward, these formulations were evaluated (in vitro and in vivo) for their potential against colorectal cancer (CRC). METHODS: The SLNs were synthesised by employing the solvent diffusion technique and then they were entrapped in the MBs. The prepared uncoupled and coupled SLNs (SLN-OP and FA-SLN-OP, respectively) were examined for in vitro cytotoxicity effect against COLO-205. Gamma-scintigraphy study was used for determining biodistribution (in vivo) of drug in different organs through MBs. RESULTS: Outcomes for FA-SLN-OP revealed more cytotoxicity (50% inhibitory concentration [IC50] = 6.8 µg/ml) against COLO-205 cells (in vitro) than OP solution (IC50 = 8.0 µg/ml) and SLN-OP (IC50= 7.5 µg/ml). MBs were also investigated in vivo using Gamma-scintigraphy study. After 48 h study, 99mTc-EuB-FA-SLN-OP confirmed an elevated level of drug in the colonic tumour, which was found significantly (p< 0.0001) higher than that of 99mTc-EuB-SLN-OP. CONCLUSIONS: In conclusion, developed MBs formulation (99mTc-EuB-FA-SLN-OP) suggested promising results against therapy of CRC using dual targeting (i.e. ligand-directed and pH-awakened) approach.

Genotypic and phenotypic variability of 22q11.2 microduplications: An institutional experience.

Duplications in the 22q11.2 region can cause 22q11.2 duplication syndrome and encompass a variety of phenotypes including developmental delays, facial abnormalities, cardiovascular defects, central nervous system delays, and other congenital abnormalities. However, the contribution of these contiguous duplicated regions to the clinical phenotypes has not been fully elucidated. In this study, we identified nine patients carrying different 22q11.2 microduplications detected by chromosomal microarray. Of these patients, seven pediatric patients presented with various clinical features including two neonate cases died shortly after birth, and two healthy adults. We examined region specific genotype-phenotype associations and found unpredictability associated with 22q11.2 duplications in these nine patients.

Irinotecan hydrochloride trihydrate loaded folic acid-tailored solid lipid nanoparticles for targeting colorectal cancer: development, characterization, and in vitro cytotoxicity study using HT-29 cells.

Aim: The aim of this investigation was to evaluate the potential of folic acid-tailored solid lipid nanoparticles (SLNs) for encapsulation as well as for in vitro cytotoxicity study of irinotecan hydrochloride trihydrate (IHT) against colorectal cancer (CRC) by using HT-29 cells. Methods: Solvent diffusion technique was employed for the preparation of SLNs. Further, the formulations were optimised via three-level, three-factor Box-Behnken design (BBD). Results: The uncoupled SLNs (IRSLNs) and folic acid-coupled SLNs (IRSLNFs) formulations revealed not only high %entrapment efficiency but also small particle size. Moreover, in vitro drug release results from IRSLNs and IRSLNFs confirmed that they followed sustained-release effect for up to 144 h. Whereas, in vitro cell viability study against HT-29 cell line suggested significantly (p < 0.05) higher cytotoxicity (IC50 = 15 µg/ml) of IRSLNFs over IRSLNs and IHT solution. Conclusions: Outcomes suggested that the engineered IRSLNFs hold great potential for targeting CRC for an extended period of time.

Transcutaneous bilirubin estimation in extremely low birth weight infants receiving phototherapy: a prospective observational study.

BACKGROUND: Measurement of transcutaneous bilirubin (TcB) is a quick, reliable and painless method to guide management of hyperbilirubinemia. Studies in term and late preterm infants have found that TcB measurements from covered areas (TcB-C) during phototherapy (PHT) co-relate well with serum bilirubin levels. Limited data exists in extremely low birth weight (ELBW) infants. METHODS: In this prospective observational study, an opaque patch was placed on the back of an ELBW infant prior to initiation of PHT. TcB-C and TcB-E (TcB from exposed area) levels were measured at birth and at 24-h intervals for 5 days. Total serum bilirubin (TSB) levels were also measured within 30 min of obtaining TcB levels. A Wilcoxon signed rank test was used for data analysis. A mixed effect model was used to adjust for repeated measurements over time. The p value < 0.05 was considered significant. RESULTS: A total of 19 infants were enrolled in the study, with a mean gestational age of 26 ± 2 weeks and mean weight 827 ± 127 g. The difference between TcB-C and TSB was 2.68 ± 2.41 mg/dl (mean ± SD, p <  0.001). In contrast, the difference between TcB-E and TSB was - 0.51 ± 1.74 mg/dl (p = 0.02). TcB-C consistently overestimates TSB, while TcB-E consistently underestimates TSB. CONCLUSIONS: During PHT exposure, TcB-C does not correlate with TSB values in ELBW infants. TcB-C levels cannot be used as a surrogate for TSB measurement in ELBW infants.

Complete coverage and covering completely: Breast feeding and complementary feeding: Knowledge, attitude, and practices of mothers.

BACKGROUND: Knowing current trends for timely comprehensive action for health promotion practices is an important prerequisite for medical practitioners and policy makers. METHODS: A survey of mothers at a Tertiary Care Hospital in central India. RESULTS: On the knowledge front >83.75% of the mothers studied showed good knowledge about breastfeeding and complementary feeding. Similar, but not as encouraging, were the results about attitude, with 76.25% of mothers having a positive attitude. The results of the practices part were varied. The WHO indicators assessed were 'early initiation of breastfeeding' (68.75%), 'exclusive breastfeeding under 6 months' (85%) (however exclusive breast feeding for first 6 months was carried out by only 36.25%), 'introduction of solid, semi-solid or soft foods' (48.75%), 'continued breastfeeding at 1 year' (63.75%) and 'continued breastfeeding at 2 years' (6.25%). CONCLUSIONS: There is a discrepancy between knowledge and practices. The exclusive breast feeding rates are far from the ideal and there is a decline of continued breast feeding beyond 15 months. This calls for sustained efforts with the aim - 'cover all and cover completely'. The ideal WHO indicator for exclusive breast feeding should be 'exclusive breastfeeding for first 6 months' which will provide information about the completeness of this ideal practice.

Minimal hepatic encephalopathy in children with chronic liver disease: Prevalence, pathogenesis and magnetic resonance-based diagnosis.

BACKGROUND & AIMS: Data on minimal hepatic encephalopathy (MHE) in children is scarce. We aimed to study MHE in children with chronic liver disease (CLD) and to validate non-invasive objective tests which can assist in its diagnosis. METHODS: We evaluated 67 children with CLD (38 boys; age 13 [7-18] years) and 37 healthy children to determine the prevalence of MHE. We also assessed the correlation of MHE with changes in brain metabolites by magnetic resonance spectroscopy (1HMRS), diffusion tensor imaging (DTI) derived metrics, blood ammonia and inflammatory cytokines (interleukin-6 [IL6], tumor necrosis factor alpha [TNF-α]). In addition, the accuracy of MR-based investigations for diagnosis of MHE in comparison to neuropsychological tests was analysed. RESULTS: Thirty-four (50.7%) children with CLD had MHE on neuropsychological tests. MHE patients had higher BA (30.5 [6-74] vs. 14 [6-66]µmol/L; p=0.02), IL-6 (8.3 [4.7-28.7] vs. 7.6 [4.7-20.7]pg/ml; p=0.4) and TNF-α (17.8 [7.8-65.5] vs. 12.8 [7.5-35]pg/ml; p=0.06) than No-MHE. 1HMRS showed higher glutamine (2.6 [2.1-3.3] vs. 2.4 [2.0-3.1]; p=0.02), and lower choline (0.20 [0.14-0.25] vs. 0.22 [0.17-0.28]; p=0.1) and myo-inositol (0.25 [0.14-0.41] vs. 0.29 [0.21-0.66]; p=0.2) in MHE patients than those without MHE. Mean diffusivity (MD) on DTI was significantly higher in 6/11 brain areas in patients with MHE vs. no MHE. Brain glutamine had a significant positive correlation with blood ammonia, IL-6, TNF-α and MD of various brain regions. Neuropsychological tests showed a negative correlation with blood ammonia, IL6, TNF-α, glutamine and MD. Frontal white matter MD had a sensitivity and specificity of 73.5% and 100% for diagnosing MHE. CONCLUSIONS: In children with CLD, 50% have MHE. There is a significant positive correlation between markers of hyperammonemia, inflammation and brain edema and these correlate negatively with neuropsychological tests. MD on DTI is a reliable tool for diagnosing MHE. LAY SUMMARY: Fifty percent of children with chronic liver disease develop minimal hepatic encephalopathy (MHE) and perform poorly on neuropsychological testing. These children have raised blood ammonia, inflammatory cytokines and mild cerebral edema on diffusion tensor imaging as compared to children without MHE. The higher the ammonia, inflammatory cytokines and cerebral edema levels the poorer the performance on neuropsychological assessment. The estimation of mean diffusivity on diffusion tensor imaging is an objective and reliable method for diagnosing MHE.

Bupropion sustained release for pregnant smokers: a randomized, placebo-controlled trial.

BACKGROUND: Bupropion is used to treat depression during pregnancy. However, its usefulness as a smoking cessation aid for pregnant women is not fully known. OBJECTIVE: The objective of the study was to evaluate the preliminary efficacy of bupropion sustained release for smoking cessation during pregnancy. STUDY DESIGN: We conducted a randomized, prospective, double-blind, placebo-controlled, pilot trial. Pregnant women who smoked daily received individualized behavior counseling and were randomly assigned to a 12 week, twice-a-day treatment with 150 mg bupropion sustained release or placebo. The primary study objectives were to determine whether bupropion sustained release reduces nicotine withdrawal symptoms on the quit date and during the treatment period compared with placebo and whether it increases 7 day point prevalence abstinence at the end of the treatment period and at the end of pregnancy. RESULTS: Subjects in the bupropion (n = 30) and placebo (n = 35) groups were comparable in age, smoking history, number of daily smoked cigarettes, and nicotine dependence. After controlling for maternal age and race, bupropion sustained release reduced cigarette cravings (1.5 ± 1.1 vs 2.1 ± 1.2, P = .02) and total nicotine withdrawal symptoms (3.8 ± 4.3 vs 5.4 ± 5.1, P = .028) during the treatment period. Administration of bupropion sustained release reduced tobacco exposure, as determined by levels of carbon monoxide in exhaled air (7.4 ± 6.4 vs 9.1 ± 5.8, P = .053) and concentrations of cotinine in urine (348 ± 384 ng/mL vs 831 ± 727 ng/mL, P = .007) and increased overall abstinence rates during treatment (19% vs 2%, P = .003). However, there was no significant difference in 7 day point prevalence abstinence rates between the 2 groups at the end of medication treatment (17% vs 3%, P = .087) and at the end of pregnancy (10% vs 3%, P = .328). CONCLUSION: Individual smoking cessation counseling along with the twice-daily use of 150 mg bupropion sustained release increased smoking cessation rates and reduced cravings and total nicotine withdrawal symptoms during the treatment period. However, there was no significant difference in abstinence rates between groups at the end of medication treatment and at the end of pregnancy, likely because of the small sample size. A larger study is needed to confirm these findings and to examine the potential benefit/ risk ratio of bupropion sustained release for smoking cessation during pregnancy.

Protective effects of amniotic fluid in the setting of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is the most common life threatening condition affecting preterm infants. NEC occurs in 1-5% of all neonatal intensive care admissions and 5-10% of very low birth weight infants. The protective role of human breast milk (BM) has been well established. It has also been shown that amniotic fluid (AF) and BM have many similarities in terms of presence of growth and other immune-modulatory factors. This finding led to the initial hypothesis that AF may exert similar protective effects against the development of NEC, as does BM. Multiple studies have elucidated the presence of growth factors in AF and the protective effect of AF against NEC. Studies have also described possible mechanisms how AF protects against NEC. At present, research in this particular area is extremely active and robust. This review summarizes the various studies looking at the protective effects of AF against the development of NEC. It also provides an insight into future directions, the vast potential of AF as a readily available biologic medium, and the ethical barriers that must be overcome before using AF.

Use of Retrospective Continuous Glucose Monitoring for Optimizing Management of Type 2 Diabetes in India.

BACKGROUND: Retrospective continuous glucose monitoring (CGM) studies may provide healthcare professionals (HCPs) with better understanding of glycemic patterns in patients with type 2 diabetes (T2D) and thereby support patient education and appropriate therapeutic interventions. METHODS: Adults with T2D and A1C values between 8% and 10% were eligible for this 3-month study. Patients were scheduled for 5 visits that included baseline and a month-2 retrospective CGM study (iPro2, Medtronic) followed by data review and therapy modifications. A1C values were determined at baseline and at study end. Questionnaires were completed at each visit. HCP questionnaires assessed perception of the utility of studies; patient questionnaires assessed understanding of the importance of compliance with HCP recommendations. Indices of glycemic variability and control were calculated from CGM data retrospectively. RESULTS: A total of 181 subjects enrolled and 148 completed the study (81.8%). There were no serious adverse device effects. Most subjects (91.2%) had > 1 therapy change after review of the first iPro2 test. Mean A1C decreased from 8.6% at baseline to 8.0% at month 3 (p<0.001). Questionnaire results from patients and HCPs indicated that both groups viewed the iPro2 studies and results as acceptable and useful. CGM-based glycemic variability metrics were similar in the two iPro2 tests. CONCLUSIONS: iPro2 studies provided HCPs with insights and opportunities for initiating changes to treatment regimens and to diet and exercise behaviors, and provided patients with improved knowledge of the importance of therapy compliance. Favorable reductions in A1C suggest that iPro2 tests can facilitate optimal management of T2D.

Lectin-Conjugated Clarithromycin and Acetohydroxamic Acid-Loaded PLGA Nanoparticles: a Novel Approach for Effective Treatment of H. pylori.

Helicobacter pylori infection remains challenging as it mainly colonized beneath the deep gastric mucosa and adheres to epithelial cells of the stomach. Concanavalin-A (Con-A)-conjugated gastro-retentive poly (lactic-co-glycolic acid) (PLGA) nanoparticles of acetohydroxamic acid (AHA) and clarithromycin (CLR) were prepared and evaluated under in vitro conditions. Solvent evaporation method was employed for preparation of nanoparticles and characterized for particle size distribution, surface morphology, percent drug entrapment, and in vitro drug release in simulated gastric fluid. Optimized nanoparticles were conjugated with Con-A and further characterized for Con-A conjugation efficiency and mucoadhesion and tested for in vitro anti-H. pylori activity. The conjugation with Con-A further sustained the drug release over a period of 8 h when compared to non-conjugated nanoparticles of AHA and CLR. In vitro anti H. pylori study confirmed that Con-A-conjugated nanoparticles containing both drugs, i.e., CLR and AHA, had shown maximum zone of inhibition compared to other formulations. In a nut shell, results suggest that the developed systems could be used for better therapeutic activity against H. pylori infection.

Intensifying Insulin Therapy in Type 2 Diabetes: Choices & Challenges.

Insulin therapy remains the cornerstone of effective diabetes management. Timely intensification of insulin therapy reduces the progression of diabetes and the development of diabetes-related complications. Given that overall hyperglycaemia is a relative contribution of both fasting and postprandial hyperglycaemia, use of basal insulin alone may not achieve optimal glucose control due to its inability to cover postprandial glucose excursions. Intensifying therapy with addition of bolus insulin or switching to premixed insulin is a viable option in patients failing on basal alone therapy. Although the benefits of early insulin treatment are well established, a considerable delay in intensifying insulin therapy in patients with sub-optimal glycaemic control is still observed. Most of the patients and physicians are reluctant to intensify therapy due to the fear of hypoglycaemia, regimen complexity, and increased burden of multiple daily injections. In this context, there is a need for a flexible, alternative intensification option taking into account individual patient considerations to achieve or maintain individual glycaemic targets. An ideal insulin regimen should mimic physiological insulin release while providing optimal glycaemic control with low risk of hypoglycaemia, weight gain and fewer daily injections. The current paper reviews the challenges of insulin intensification in patients with type 2 diabetes mellitus poorly controlled on current treatment regimens.

Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis.

Fetal swallowing of amniotic fluid, which contains numerous cytokines and growth factors, plays a key role in gut mucosal development. Preterm birth interrupts this exposure to amniotic fluid-borne growth factors, possibly contributing to the increased risk of necrotizing enterocolitis (NEC) in premature infants. We hypothesized that supplementation of formula feeds with amniotic fluid can provide amniotic fluid-borne growth factors and prevent experimental NEC in rat pups. We compared NEC-like injury in rat pups fed with infant formula vs. formula supplemented either with 30% amniotic fluid or recombinant hepatocyte growth factor (HGF). Cytokines/growth factors in amniotic fluid were measured by immunoassays. Amniotic fluid and HGF effects on enterocyte migration, proliferation, and survival were measured in cultured IEC6 intestinal epithelial cells. Finally, we used an antibody array to investigate receptor tyrosine kinase (RTK) activation and immunoblots to measure phosphoinositide 3-kinase (PI3K) signaling. Amniotic fluid supplementation in oral feeds protected rat pups against NEC-like injury. HGF was the most abundant growth factor in rat amniotic fluid in our panel of analytes. Amniotic fluid increased cell migration, proliferation, and cell survival in vitro. These effects were reproduced by HGF and blocked by anti-HGF antibody or a PI3K inhibitor. HGF transactivated several RTKs in IEC6 cells, indicating that its effects extended to multiple signaling pathways. Finally, similar to amniotic fluid, recombinant HGF also reduced the frequency and severity of NEC-like injury in rat pups. Amniotic fluid supplementation protects rat pups against experimental NEC, which is mediated, at least in part, by HGF.

Efficacy without barriers to insulin therapy: lessons from the BEGIN trial programme.

Insulin degludec has been extensively studied in the BEGIN programme in a range of patients with type 1 or type 2 diabetes. The programme includes insulin-naive type 2 diabetes, insulin-treated type 2 and type 1 diabetes which are investigated as basal-bolus therapy, basal plus oral therapy, and basal vs. oral therapy and also the flexible dosing options. In all insulin degludec phase 3 trials, the efficacy of once daily insulin degludec was established, as insulin degludec being non-inferior to comparators in reducing HbA(1c). Also the flexible dosing option is an attractive feature of this insulin that mightimprove adherence to therapy and conceivably improve outcomes.