Comparative Efficacy and Safety of Neuroprotective Therapies for Neonates With Hypoxic Ischemic Encephalopathy: A Network Meta-Analysis.

Context: Several interventions are available for the management of hypoxic ischemic encephalopathy (HIE), but no studies have compared their relative efficacy in a single analysis. This study aims to compare and determine the effectiveness of available interventions for HIE using direct and indirect data. Methods: Large randomized trials were identified from PubMed, EMBASE, CINAHL Plus, AMED, and Cochrane Library of Clinical Trials database from inception until June 30, 2018. Two independent reviewers extracted study data and performed quality assessment. Direct and network meta-analysis of randomized controlled trials was performed to obtained pooled results comparing the effectiveness of different therapies used in HIE on mortality, neurodevelopmental delay at 18 months, as well as adverse events. Their probability of having the highest efficacy and safety was estimated and ranked. The certainty of evidence for the primary outcomes of mortality and mortality or neurodevelopmental delay at 18 months was evaluated using GRADE criteria. Results: Fifteen studies comparing five interventions were included in the network meta-analysis. Whole body cooling [Odds ratio: 0.62 (95% credible interval: 0.46-0.83); 8 trials, high certainty of evidence] was the most effective treatment in reducing the risk of mortality, followed by selective head cooling (0.73; 0.48-1.11; 2 trials, moderate certainty of evidence) and use of magnesium sulfate (0.79; 0.20-3.06; 2 trials, low certainty of evidence). Whole body hypothermia (0.48; 0.33-0.71; 5 trials), selective head hypothermia (0.54; 0.32-0.89; 2 trials), and erythropoietin (0.36; 0.19-0.66; 2 trials) were more effective for reducing the risk of mortality and neurodevelopmental delay at 18 months (moderate to high certainty). Among neonates treated for HIE, the use of erythropoietin (0.36; 0.18-0.74, 2 trials) and whole body hypothermia (0.61; 0.45-0.83; 7 trials) were associated with lower rates of cerebral palsy. Similarly, there were lower rates of seizures among neonates treated with erythropoietin (0.35; 0.13-0.94; 1 trial) and whole body hypothermia (0.64; 0.46-0.87, 7 trials). Conclusion: The findings support current guidelines using therapeutic hypothermia in neonates with HIE. However, more trials are needed to determine the role of adjuvant therapy to hypothermia in reducing the risk of mortality and/or neurodevelopmental delay.

Altering calcium and phosphorus levels in utero affects adult mouse mandibular morphology.

OBJECTIVES: The purpose of our study was to determine morphological changes and bone mineral density (BMD) differences in the adult mandible of offspring exposed to high calcium, low phosphorus diets in utero until weaning age. MATERIALS AND METHODS: Time-mated FVB wild-type mice were fed normal or experimental diet during gestation and until weaning of offspring. Experimental diet contained 3-fold increase in calcium and 3-fold decrease in phosphorus compared to normal diet. Adult mandibles of offspring exposed to experimental diet were sacrificed and heads scanned using micro-computed tomography. Three-dimensional 3D geometric morphometric analysis GMA was utilized to detect morphological changes to the mandible including the condyle. RESULTS: Experimental females showed the greatest morphological differences including shortened mandibular ramus width and height, shortened mandibular body length and height, a wider but shortened condylar neck and a wider condylar head in the lateral-medial direction. Experimental male mandibles trended towards increased mandibular body height and length, opposite the changes observed in experimental female mandibles, whereas condyles were similar to that observed in experimental females. Bone mineral density (BMD) was lowered in experimental females. CONCLUSION: Increased calcium and decreased phosphorus levels led to a retrognathic mandible associated with lowered BMD in experimental females, whereas experimental showed partly opposite effects. Further studies are required to understand the mechanism underlying diet- and gender-specific differences in mandibular morphology.

The effect of vitamin D supplementation on glucose metabolism in type 2 diabetes mellitus: A systematic review and meta-analysis of intervention studies.

AIMS: We aimed to assess whether vitamin D supplementation improves glucose metabolism in adults with type 2 diabetes. METHODS: PubMed and Cochrane database were searched up to July 1st 2016 for randomized controlled trials that assessed the relationship between vitamin D supplementation and glucose metabolism (change in hemoglobin A1C (HbA1C) and fasting blood glucose (FBG)) among adults with type 2 diabetes. RESULTS: Twenty nine trials (3324 participants) were included in the systematic review. Among 22 studies included in the meta-analysis, 19 reported HbA1C, 16 reported FBG outcomes and 15 were deemed poor quality. There was a modest reduction in HbA1C (-0.32% [-0.53 to -0.10], I2=91.9%) compared to placebo after vitamin D supplementation but no effect on FBG (-2.33mg/dl [-6.62 to 1.95], I2=59.2%). In studies achieving repletion of vitamin D deficiency (n=7), there were greater mean reductions in HbA1C (-0.45%, [-1.09 to 0.20]) and FBG (-7.64mg/dl [-16.25 to 0.97]) although not significant. CONCLUSIONS: We found a modest reduction of HbA1C after vitamin D treatment in adults with type 2 diabetes albeit with substantial heterogeneity between studies and no difference in FBG. Larger studies are needed to further evaluate the glycemic effects of vitamin D treatment especially in patients with vitamin D deficiency.

Evaluation of the Association Between Preoperative Clinical Factors and Long-term Weight Loss After Roux-en-Y Gastric Bypass.

Importance: Weight loss after bariatric surgery varies, yet preoperative clinical factors associated with long-term suboptimal outcomes are not well understood. Objective: To evaluate the association between preoperative clinical factors and long-term weight loss after Roux-en-Y gastric bypass (RYGB). Design, Setting, and Participants: From June 2001 to September 2007, this retrospective cohort study followed up RYGB patients before surgery to 7 to 12 years after surgery. The setting was a large rural integrated health system. Of 1033 eligible RYGB patients who consented to participate in longitudinal research and completed surgery before October 2007, a total of 726 (70.3%) had a weight entered in the electronic medical record 7 or more years after surgery and were included in the analyses after exclusions for pregnancy and mortality. Date of the long-term weight measurement was recorded between August 2010 and January 2016. Main Outcomes and Measures: The primary outcome was percentage weight loss (%WL) at 7 to 12 years after surgery. Preoperative clinical factors (>200) extracted from the electronic medical record included medications, comorbidities, laboratory test results, and demographics, among others. Results: Among the 726 study participants, 83.1% (n = 603) were female and 97.4% (n = 707) were of white race, with a mean (SD) preoperative body mass index (calculated as weight in kilograms divided by height in meters squared) of 47.5 (7.4). From the time of surgery to long-term follow-up (median, 9.3 postoperative years), the mean (SD) %WL was 22.5% (13.1%). Preoperative insulin use, history of smoking, and use of 12 or more medications before surgery were associated with greater long-term postoperative %WL (6.8%, 2.8%, and 3.1%, respectively). Preoperative hyperlipidemia, older age, and higher body mass index were associated with poorer long-term postoperative %WL (-2.8%, -8.8%, and -4.1%, respectively). Conclusions and Relevance: Few preoperative clinical factors associated with long-term weight loss after RYGB were identified. Preoperative insulin use was strongly associated with better long-term %WL, while preoperative hyperlipidemia, higher body mass index, and older age were associated with poorer %WL. Our findings provide additional insight into preoperative identification of RYGB patients at higher risk for long-term suboptimal outcomes.

The substrate capture mechanism of Mycobacterium tuberculosis anthranilate phosphoribosyltransferase provides a mode for inhibition.

Anthranilate phosphoribosyltransferase (AnPRT, EC 2.4.2.18) is a homodimeric enzyme that catalyzes the reaction between 5'-phosphoribosyl 1'-pyrophosphate (PRPP) and anthranilate, as part of the tryptophan biosynthesis pathway. Here we present the results of the first chemical screen for inhibitors against Mycobacterium tuberculosis AnPRT (Mtb-AnPRT), along with crystal structures of Mtb-AnPRT in complex with PRPP and several inhibitors. Previous work revealed that PRPP is bound at the base of a deep cleft in Mtb-AnPRT and predicted two anthranilate binding sites along the tunnel leading to the PRPP binding site. Unexpectedly, the inhibitors presented here almost exclusively bound at the entrance of the tunnel, in the presumed noncatalytic anthranilate binding site, previously hypothesized to have a role in substrate capture. The potencies of the inhibitors were measured, yielding Ki values of 1.5-119 µM, with the strongest inhibition displayed by a bianthranilate compound that makes hydrogen bond and salt bridge contacts with Mtb-AnPRT via its carboxyl groups. Our results reveal how the substrate capture mechanism of AnPRT can be exploited to inhibit the enzyme's activity and provide a scaffold for the design of improved Mtb-AnPRT inhibitors that may ultimately form the basis of new antituberculosis drugs with a novel mode of action.