Visceral fat mass as a novel risk factor for predicting gestational diabetes in obese pregnant women

Objective To develop a model to predict gestational diabetes mellitus incorporating classical and a novel risk factor, visceral fat mass. Methods Three hundred two obese non-diabetic pregnant women underwent body composition analysis at booking by bioimpedance analysis. Of this cohort, 72 (24%) developed gestational diabetes mellitus. Principal component analysis was initially performed to identify possible clustering of the gestational diabetes mellitus and non-GDM groups. A machine learning algorithm was then applied to develop a GDM predictive model utilising random forest and decision tree modelling. Results The predictive model was trained on 227 samples and validated using an independent testing subset of 75 samples where the model achieved a validation prediction accuracy of 77.53%. According to the decision tree developed, visceral fat mass emerged as the most important variable in determining the risk of gestational diabetes mellitus. Conclusions We present a model incorporating visceral fat mass, which is a novel risk factor in predicting gestational diabetes mellitus in obese pregnant wome

Metformin versus placebo in obese pregnant women without diabetes mellitus

Background: Obesity is associated with increased risk of adverse pregnancy outcomes. Lifestyle intervention studies have not improved outcome. Metformin improves insulin sensitivity and leads to less weight gain. Methods: Our double-blind placebo-controlled trial randomized non-diabetic pregnant women with a body mass index >35 kg/m2 to metformin or placebo from 12-18 weeks’ gestation until delivery. Primary outcome was median neonatal birth weight z-score reduction by 0.3 standard deviations (equivalent to a 50% reduction in incidence of large-for-gestational-age neonates from 20% to 10%). Secondary outcomes included maternal gestational weight gain and incidence of gestational diabetes, and preeclampsia, as well as adverse neonatal outcomes. Women were randomized, by computer generated random numbers, to either daily metformin 3.0 grams (n=225) or to placebo (n=225). Analysis was by intention to treat. Results: Fifty women withdrew consent, leaving 202 in the metformin group and 198 in the placebo group. There was no significant difference in median neonatal birth weight z-score (metformin: 0.05, IQR -0.71 to 0.92; placebo: 0.17, IQR -0.62 to 0.89; p=0.655). In the metformin group, compared to placebo, median maternal gestational weight gain was lower (4.6 kg, IQR 1.3-7.2 vs. 6.3 kg, IQR 2.9-9.2, p<0.0001) and incidence of preeclampsia was lower (3.0% vs 11.3%; odds ratio 0.24, 95% CI 0.10-0.61; p=0.001), incidence of side effects was higher; there were no significant differences in gestational diabetes, large for gestational age neonates and adverse neonatal outcomes. Conclusions: In non-diabetic women with BMI >35 kg/m2, antenatal administration of metformin reduces maternal weight gain but not neonatal birth weight. (ClinicalTrials.gov number, NCT01273584

EFFECTS OF NITROXAZEPINE ON DIASTOLIC BLOOD PRESSURE IN MILD HYPERTENSIVE PATIENTS -A SHORT TERM CLINICAL STUDY

Abstract: In a double blind short term clinical study, nitroxazcpine has been found to be superior over placebo in reducing the diastolic blood pressure in mild hypertensive patients. In short term open clinical trial design nitroxazepine (25 mg PO, HS) has been found to be superior and better tolerated than diazepam (5 mg PO, HS). In open clinical trial design. nitroxazepine (25 mg PO, HS) reduced the diastolic blood pressure to the target level (100 mm Hg and less) effecti&apos;.&apos;ely controlling the uncontrolled hypertensive patients receiving maintenance dose of beta blockers. There was no such beneficial effect in patients receiving maintenance doses of other antihypertensive drugs (piLot studyl. Adverse drug reactions like disturbed sleep in one, uneasiness in 3, palpitation in one and dryness of mouth in one patient have been observed

Quantitative Prediction and Clinical Observation of a CYP3A Inhibitor-Based Drug-Drug Interactions with MLN3897, a Potent C-C Chemokine Receptor-1 Antagonist

ABSTRACT A novel in vitro model was recently developed in our laboratories for the prediction of magnitude of clinical pharmacokinetic drugdrug interactions (DDIs), based on reversible hepatic cytochrome P450 (P450) inhibition. This approach, using inhibition data from human hepatocytes incubated in human plasma, and quantitative P450 phenotyping data from hepatic microsomal incubations, successfully predicted DDIs for 15 marketed drugs with ketoconazole, a strong competitive inhibitor of CYP3A4/5, generally used to demonstrate a &quot;worst-case scenario&quot; for CYP3A inhibition. In addition, this approach was successfully extended to DDI predictions with the moderate competitive CYP3A inhibitor fluconazole for nine marketed drugs. In the current report, the general applicability of the model has been demonstrated by prospectively predicting the degree of inhibition and then conducting DDI studies in the clinic for an investigational CCR1 antagonist MLN3897, which is cleared predominantly by CYP3A. The clinical studies involved treatment of healthy volunteers (n ϭ 17-20), in a crossover design, with ketoconazole (200 mg b.i.d.) or fluconazole (400 mg once a day), while receiving MLN3897. Administration of MLN3897 and ketoconazole led to an average 8.28-fold increase in area under the curve of plasma concentration-time plot (AUC) of MLN3897 at steady state, compared with the 8.33-fold increase predicted from the in vitro data. Similarly for fluconazole, an average increase of 3.93-fold in AUC was observed for MLN3897 in comparison with a predicted value of 3.26-fold. Thus, our model reliably predicted the exposure changes for MLN3897 in interaction studies with competitive CYP3A inhibitors in humans, further strengthening the utility of our in vitro model. Prediction of clinical DDIs using in vitro studies is one of the major challenges in the pharmaceutical industry. The main utility of such DDI predictions is to help foresee any safety issues anticipated from higher exposures and thus help design clinical trials with better safety. In some instances, clinical DDI studies can be avoided if no significant pharmacokinetic interaction is predicted. Traditionally, DDI predictions have been based on the ratio of the inhibitor concentration [I] and the enzyme inhibition constant K i ([I]/K i ratio

Remdesivir Versus Standard-of-Care for Severe Coronavirus Disease 2019 Infection: An Analysis of 28-Day Mortality

BACKGROUND: Remdesivir is FDA approved for the treatment of hospitalized patients with COVID-19 and has been shown to shorten time to recovery and improve clinical outcomes in randomized trials. METHODS: This was the final day 28 comparative analysis of data from a phase 3, randomized, open-label study comparing 2 remdesivir regimens (5 vs 10 days, combined for this analysis [remdesivir cohort]) and a real-world retrospective longitudinal cohort study of patients receiving standard-of-care treatment (non-remdesivir cohort). Eligible patients, aged ≥18 years, had confirmed SARSCoV-2, oxygen saturation ≤94% on room air or required supplemental oxygen, with pulmonary infiltrates. Propensity score matching (up to 1:10 ratio) was used to ensure comparable populations. We assessed day 14 clinical recovery (determined using a 7-point ordinal scale) and day 28 all-cause mortality (coprimary endpoints). RESULTS: Altogether, 368 (remdesivir) and 1399 (non-remdesivir) patients were included in the matched analysis. The day 14 clinical recovery rate was significantly higher among the remdesivir versus the non-remdesivir cohort (65.2% vs 57.1%; OR 1.49, 95% CI 1.16–1.90; P = .002). The day 28 mortality rate was significantly lower in the remdesivir cohort versus the non-remdesivir cohort (12.0% vs 16.2%; OR 0.67, 95% CI 0.47–0.95; P = .03). CONCLUSIONS: Remdesivir was associated with significantly higher rates of day 14 clinical recovery, and lower day 28 mortality, compared with standard-of-care treatment in hospitalized patients with COVID-19. Collectively, these data support the use of remdesivir to improve clinical recovery and decrease mortality from SARS-CoV-2 infection

Contemporary snapshot of tumor regression grade (TRG) distribution in locally advanced rectal cancer: a cross sectional multicentric experience.

Pre-operative chemoradiotherapy (CRT) followed by surgical resection is still the standard treatment for locally advanced low rectal cancer. Nowadays new strategies are emerging to treat patients with a complete response to pre-operative treatment, rendering the optimal management still controversial and under debate. The primary aim of this study was to obtain a snapshot of tumor regression grade (TRG) distribution after standard CRT. Second, we aimed to identify a correlation between clinical tumor stage (cT) and TRG, and to define the accuracy of magnetic resonance imaging (MRI) in the restaging setting. Between January 2017 and June 2019, a cross sectional multicentric study was performed in 22 referral centers of colon-rectal surgery including all patients with cT3-4Nx/cTxN1-2 rectal cancer who underwent pre-operative CRT. Shapiro-Wilk test was used for continuous data. Categorical variables were compared with Chi-squared test or Fisher's exact test, where appropriate. Accuracy of restaging MRI in the identification of pathologic complete response (pCR) was determined evaluating the correspondence with the histopathological examination of surgical specimens.In the present study, 689 patients were enrolled. Complete tumor regression rate was 16.9%. The "watch and wait" strategy was applied in 4.3% of TRG4 patients. A clinical correlation between more advanced tumors and moderate to absent tumor regression was found (p = 0.03). Post-neoadjuvant MRI had low sensibility (55%) and high specificity (83%) with accuracy of 82.8% in identifying TRG4 and pCR.Our data provided a contemporary description of the effects of pre-operative CRT on a large pool of locally advanced low rectal cancer patients treated in different colon-rectal surgical centers

Colorectal cancer after bariatric surgery (Cric-Abs 2020): Sicob (Italian society of obesity surgery) endorsed national survey

Background: The published colorectal cancer (CRC) outcomes after bariatric surgery (BS) are conflicting, with some anecdotal studies reporting increased risks. The present nationwide survey CRIC-ABS 2020 (Colo-Rectal Cancer Incidence-After Bariatric Surgery-2020), endorsed by the Italian Society of Obesity Surgery (SICOB), aims to report its incidence in Italy after BS, comparing the two commonest laparoscopic procedures—Sleeve Gastrectomy (SG) and Roux-en-Y gastric bypass (GBP). Methods: Two online questionnaires—first having 11 questions on SG/GBP frequency with a follow-up of 5–10 years, and the second containing 15 questions on CRC incidence and management, were administered to 53 referral bariatric, high volume centers. A standardized incidence ratio (SIR—a ratio of the observed number of cases to the expected number) with 95% confidence intervals (CI) was calculated along with CRC incidence risk computation for baseline characteristics. Results: Data for 20,571 patients from 34 (63%) centers between 2010 and 2015 were collected, of which 14,431 had SG (70%) and 6140 GBP (30%). 22 patients (0.10%, mean age = 53 ± 12 years, 13 males), SG: 12 and GBP: 10, developed CRC after 4.3 ± 2.3 years. Overall incidence was higher among males for both groups (SG: 0.15% vs 0.05%; GBP: 0.35% vs 0.09%) and the GBP cohort having slightly older patients. The right colon was most affected (n = 13) and SIR categorized/sex had fewer values < 1, except for GBP males (SIR = 1.07). Conclusion: Low CRC incidence after BS at 10 years (0.10%), and no difference between procedures was seen, suggesting that BS does not trigger the neoplasm development