The Metabolomic-Gut-Clinical Axis of Mankai Plant-Derived Dietary Polyphenols

Background: Polyphenols are secondary metabolites produced by plants to defend themselves from environmental stressors. We explored the effect of Wolffia globosa ‘Mankai’, a novel cultivated strain of a polyphenol-rich aquatic plant, on the metabolomic-gut clinical axis in vitro, in-vivo and in a clinical trial. Methods: We used mass-spectrometry-based metabolomics methods from three laboratories to detect Mankai phenolic metabolites and examined predicted functional pathways in a Mankai artificial-gut bioreactor. Plasma and urine polyphenols were assessed among the 294 DIRECT-PLUS 18-month trial participants, comparing the effect of a polyphenol-rich green-Mediterranean diet (+1240 mg/polyphenols/day, provided by Mankai, green tea and walnuts) to a walnuts-enriched (+440 mg/polyphenols/day) Mediterranean diet and a healthy controlled diet. Results: Approximately 200 different phenolic compounds were specifically detected in the Mankai plant. The Mankai-supplemented bioreactor artificial gut displayed a significantly higher relative-abundance of 16S-rRNA bacterial gene sequences encoding for enzymes involved in phenolic compound degradation. In humans, several Mankai-related plasma and urine polyphenols were differentially elevated in the green Mediterranean group compared with the other groups (p < 0.05) after six and 18 months of intervention (e.g., urine hydroxy-phenyl-acetic-acid and urolithin-A; plasma Naringenin and 2,5-diOH-benzoic-acid). Specific polyphenols, such as urolithin-A and 4-ethylphenol, were directly involved with clinical weight-related changes. Conclusions: The Mankai new plant is rich in various unique potent polyphenols, potentially affecting the metabolomic-gut-clinical axis.

Efficacy and Safety of Tetrahydrocurcuminoids for the Treatment of Canker Sore and Gingivitis

Background. Tetrahydrocurcuminoids (THCs) are among the major metabolites of curcuminoids with a higher bioavailability and physiological stability and exhibit a broad spectrum of therapeutic activities. The objective of this study was to evaluate the efficacy of THCs in patients suffering from canker sore and gingivitis designed as an exploratory clinical trial. Methods. This is an open label prospective pilot clinical trial carried out at two clinical centers: Noble Hospital, Pune, Maharashtra, and Sri Venkateshwara Hospital, Bangalore, Karnataka in India. Participants were assigned to 21 days of treatment with chewable oral THCs supplement. Patients were instructed to self-administer one chewable tablet containing 100 mg of THCs twice daily for up to 21 days. This clinical trial was registered at a public Clinical Trial Registry in India (http://www.ctri.nic.in). Thirty-one canker sore and twenty-nine gingivitis patients participated in this study. Body mass index, throat numbness/relief, Visual Analog Scale (VAS) pain score, canker sore lesions, gingival appearance, inflammation and bleeding were assessed before and after treatment, at 14 and 21 days. Vital signs and laboratory parameters were assessed for safety. Results. THCs treatment significantly reduced the reddening at the site, difficulty in chewing, swallowing, and VAS pain score in the canker sore patients. Further, both single and multiple lesions were completely healed. In gingivitis patients, gingival appearance, bleeding, and inflammation were significantly reduced. No adverse effects were observed during the study. Conclusion. Overall, the findings of this study show that supplementation of THCs for 21 days reduced the pain and prevented the progression of the disease in patients suffering from canker sore and gingivitis without adverse side effects.

The Use of Digital Clinical Trial Methods in the Evaluation of Digital Therapeutics: A Scoping Review (Preprint)

BACKGROUND Digital Therapeutics (DTx) provide evidence based therapeutic health interventions that have been clinically validated to deliver therapeutic outcomes, such that the software is the treatment. Digital methodologies are increasingly adopted to conduct clinical trials due to advantages they provide including increases in efficiency and decreases in trial costs. Digital therapeutics are digital by design and can leverage the potential of digital and remote clinical trial methods. OBJECTIVE The principal purpose of this scoping review is to review the literature to determine whether digital technologies are being used in DTx clinical research, which type are being used and whether publications are noting any advantages to their use. As DTx development is an emerging field there are likely gaps in the knowledge base regarding DTx and clinical trials, and the purpose of this review is to illuminate those gaps. A secondary purpose is to consider questions which emerged during the review process including whether fully remote digital clinical research is appropriate for all health conditions and whether digital clinical trial methods are inline with the principles of Good Clinical Practice. METHODS 1,326 records were identified by searching research databases and 1,227 reviewed at the full-article level in order to determine if they were appropriate for inclusion. Confirmation of clinical trial status, use of digital clinical research methods and digital therapeutic status as well as inclusion and exclusion criteria were applied in order to determine relevant articles. Digital methods employed in DTx research were extracted from each article and these data were synthesized in order to determine which digital methods are currently used in clinical trial research. RESULTS After applying our criteria for scoping review inclusion, 11 articles were identified. All articles used at least one form of digital clinical research methodology enabling an element of remote research. The most commonly used digital methods are those related to recruitment, enrollment and the assessment of outcomes. A small number of articles reported using other methods such as online compensation (n = 3), or digital reminders for participants (n = 5). The majority of digital therapeutics clinical research using digital methods is conducted in the United States and increasing number of articles using digital methods are published each year. CONCLUSIONS Digital methods are used in clinical trial research evaluating DTx, though not frequently as evidenced by the low proportion of articles included in this review. Fully remote clinical trial research is not yet the standard, more frequently authors are using partially remote methods. Additionally, there is tremendous variability in the level of detail describing digital methods within the literature. As digital technologies continue to advance and the clinical research DTx literature matures, digital methods which facilitate remote research may be used more frequently.

Bilevel positive airway pressure in two moments after bariatric surgery

SUMMARY OBJECTIVE To investigate the use of Bilevel Positive Airway Pressure (BiPAP) in morbidly obese individuals in two moments following bariatric surgery (Roux-en-Y gastric bypass): post-anesthetic recovery (PAR) and first postoperative day (1PO). DESIGN Randomized and blinded clinical trial. METHODS We studied 40 morbidly obese individuals aged between 25 and 55 years who underwent pulmonary function test and chest X-ray preoperatively, and on the day of discharge (2nd day after surgery). They were randomly allocated into two groups: PAR-G (BiPAP in PAR for one hour), and 1PO-G (BIPAP for one hour on the 1PO). RESULTS In the PAR-G and 1PO-G, respectively there were significant reductions in slow vital capacity (SVC) (p=0.0007 vs. p<0.0001), inspiratory reserve volume (IRV) (p=0.0016 vs. p=0.0026), and forced vital capacity (FVC) (p=0.0013 vs. p<0.0001) and expiratory reserve volume (ERV) was maintained only for the PAR-G (p=0.4446 vs. p=0.0191). Comparing the groups, the SVC (p=0.0027) and FVC (p=0.0028) showed a significant difference between the treatments, while the PAR-G showed smaller declines in these capacities. The prevalence of atelectasis was 10% for the PAR-G and 30% for the 1PO-G (p=0.0027). CONCLUSION Thus, the use of BiPAP in PAR can promote restoration of ERV and contribute to the reduction of atelectasis.

Population kinetics of progression free survival (PFS).

e18251 Background: We assessed drug type impact on whether PFS curves could be fit by 2 phase decay models on nonlinear regression analysis (NLRA). Methods: We digitized 894 published PFS curves for incurable cancers. We used GraphPad Prism 7 for 1 phase and 2 phase decay NLRA, with constraints Y0 = 100 and plateau = 0. We defined curves as fitting 2 phase models if each subpopulation was ≥1% of the entire population and if subpopulation half-lives differed by a factor of ≥2, or if log-linear plots demonstrated unequivocal 2 phase decay. Results: PFS curves for single agents showed either high (≥75%) or low ( < 30%) probability of 2 phase decay, depending on drug type (p < 0.0001, Table). 11/11 PD1/ipilimumab combinations had 2 phase decay vs 36/209 curves (17%) for all other combinations. Conclusions: Drugs have either high or low probability of PFS curve 2 phase decay. Clinical trial methods or some mechanisms of acquired resistance might contribute to 2 phase decay, but 2 phase decay also could indicate a dichotomous factor (eg gene mutation/deletion or complete pathway silencing) producing 2 distinct subpopulations with differing progression rates. Drugs with high 2 phase decay could be prime candidates for RNA & whole genome sequencing, pathway expression studies etc to identify dichotomous predictive factors. Further assessment is needed to better understand why some drugs behave differently when given in combinations vs as single agents. [Table: see text]

Can an informative video about the anesthesia technique be an effective tool to treat preoperative anxiety in patients undergoing minor, elective, outpatient hand surgery procedures?

Background Preoperative anxiety is a common problem with an impact on surgical outcome, anesthetic drug amount and patient’s satisfaction. An important component of preoperative anxiety is worries related to anesthesia. Suitable patients information has been shown to reduce preoperative anxiety level and this can be effectively achieved through a video. Objectives To assess the impact of an informative video about regional intra-venous anesthesia technique on patient’s preoperative anxiety levels before minor ambulatory hand surgery procedures. Study design retrospective, single-centre, case-control clinical trial. Methods To assess the impact of an educational video illustrating all the passages of intravenous regional anesthesia on preoperative anxiety level and overall patients’ satisfaction. Results Anxiety level measured after admission in the day hospital clinic did not differ between the two groups, however overall patients’ satisfaction levels were higher when patients were shown the video. Conclusions Informative videos does not seem to significantly reduce preoperative anxiety but have the potential to increase patients’ satisfaction in the ambulatory setting.

The Best Approach for Laparoscopic Fluorescence Cholangiography: Overview of the Literature and Optimization of Dose and Dosing Time

Background: Fluorescence cholangiography using indocyanine green (ICG) can enhance orientation of bile duct anatomy during laparoscopic cholecystectomy. To ensure clear discrimination between bile ducts and liver, the fluorescence ratio between both should be sufficient. This ratio is influenced by the ICG dose and timing of fluorescence imaging. We first systematically identified all strategies for fluorescence cholangiography. Second, we aimed to optimize the dose of ICG and dosing time in a prospective clinical trial. Methods: PubMed was searched for clinical trials studying fluorescence cholangiography. Furthermore, 28 patients planned to undergo laparoscopic cholecystectomy were divided into 7 groups, receiving different intravenous doses (5 or 10 mg ICG) at different time points (0.5, 2, 4, 6, or 24 hours prior to surgery). Results: The systematic review revealed 27 trials including 1057 patients. The majority of studies used 2.5 mg administered within 1 hour before imaging. Imaging 3 to 24 hours after ICG administration was never studied. The clinical trial demonstrated that the highest bile duct-to-liver ratio was achieved 3 to 7 hours after administration of 5 mg and 5 to 25 hours after administration of 10 mg ICG. Up to 3 hours after administration of 5 mg and up to 5 hours after administration of 10 mg ICG, the liver was equally or more fluorescent than the cystic duct, resulting in a ratio ≤1.0. Conclusion: This study shows for the first time that the interval between ICG administration and intraoperative fluorescence cholangiography should be extended. Administering 5 mg ICG at least 3 hours before imaging is easy to implement in everyday clinical practice and results in bile duct-to-liver ratios >1.0.

Pre-Stroke Use of Beta-Blockers Does Not Lower Post-Stroke Infection Rate: An Exploratory Analysis of the Preventive Antibiotics in Stroke Study

Background: Stroke-associated infections occur frequently and are associated with unfavorable outcome. Previous cohort studies suggest a protective effect of beta-blockers (BBs) against infections. A sympathetic drive may increase immune suppression and infections. Aim: This study is aimed at investigating the association between BB treatment at baseline and post-stroke infection in the Preventive Antibiotics in Stroke Study (PASS), a prospective clinical trial. Methods: We performed an exploratory analysis in PASS, 2,538 patients with acute phase of stroke (24 h after onset) were randomized to ceftriaxone (intravenous, 2 g per day for 4 days) in addition to stroke unit care, or standard stroke unit care without preventive antibiotic treatment. All clinical data, including use of BBs, was prospectively collected. Infection was diagnosed by the treating physician, and independently by an expert panel blinded for all other data. Multivariable analysis was performed to investigate the relation between BB treatment and infection rate. Results: Infection, as defined by the physician, occurred in 348 of 2,538 patients (14%). Multivariable analysis showed that the use of BBs at baseline was associated with the development of infection during clinical course (adjusted OR (aOR) 1.61, 95% CI 1.19-2.18; p < 0.01). BB use at baseline was also associated with the development of pneumonia (aOR 1.56, 95% CI 1.05-2.30; p = 0.03). Baseline BB use was not associated with mortality (aOR 1.14, 95% CI 0.84-1.53; p = 0.41) or unfavorable outcome at 3 months (aOR 1.10, 95% CI 0.89-1.35; p = 0.39). Conclusions: Patients treated with BBs prior to stroke have a higher rate of infection and pneumonia.