Reducing Postoperative Opioids After Minimally Invasive Gynecologic Surgery with Multimodal Pain Control

Introduction: We evaluated the efficacy of a multimodal pain regimen that approaches pain control by utilizing different mechanisms of action. This novel protocol utilizing liposomal bupivacaine, acetaminophen, tramadol and oxycodone as needed in reducing the overall opioid use by patients after undergoing robotic-assisted total laparoscopic hysterectomy in an obese population that is heavily afflicted by the opioid epidemic. Materials and Methods: We conducted a retrospective study wherein a sample of 100 (50 multimodal group and 50 controls) were taken from 433 eligible cases conducted over a 1 year period. Patient medical records were evaluated for demographics, surgical characteristics, opioid type and dose, pain scores, length of stay and complications. Opioids were converted to oral morphine dose equivalents. Results: Overall opioid use in the multimodal group decreased by 54% (75.1mg versus 35.5mg, p Discussion: A multimodal approach to pain control is an acceptable alternative to traditional methods of pain control, regardless of BMI, for those with benign or malignant disease and decreases opioid use by 44 to 62 percent with no concomitant increase in pain scores and may decrease pain by 9 to 24 percent

Reducing Postoperative Opioids After Minimally Invasive Gynecologic Surgery with Multimodal Pain Control

Introduction: We evaluated the efficacy of a multimodal pain regimen that approaches pain control by utilizing different mechanisms of action. This novel protocol utilizing liposomal bupivacaine, acetaminophen, tramadol and oxycodone as needed in reducing the overall opioid use by patients after undergoing robotic-assisted total laparoscopic hysterectomy in an obese population that is heavily afflicted by the opioid epidemic. Materials and Methods: We conducted a retrospective study wherein a sample of 100 (50 multimodal group and 50 controls) were taken from 433 eligible cases conducted over a 1 year period. Patient medical records were evaluated for demographics, surgical characteristics, opioid type and dose, pain scores, length of stay and complications. Opioids were converted to oral morphine dose equivalents. Results: Overall opioid use in the multimodal group decreased by 54% (75.1mg versus 35.5mg, p Discussion: A multimodal approach to pain control is an acceptable alternative to traditional methods of pain control, regardless of BMI, for those with benign or malignant disease and decreases opioid use by 44 to 62 percent with no concomitant increase in pain scores and may decrease pain by 9 to 24 percent

Direct Numerical Simulation of Transverse Ripples: 2. Self-Similarity, Bedform Coarsening, and Effect of Neighboring Structures

Coupled bed-flow direct numerical simulations investigating the early stages of pattern formation and bedform (ripple) interactions were examined in a previous paper (Part 1), making use of the resolved flow field. In this paper (Part 2), we compare our results to published experimental data and provide an extensive quantitative analysis of the bed using spectral analysis and two-point correlations. The effect of the mobile rippled bed on the flow structure and turbulence is investigated locally (at specific streamwise locations) and over the entire computational domain. We show that developing ripples attain a self-similar profile in both the shape and the corresponding bed shear stress. We demonstrate the importance of neighboring structures, especially upstream neighbors, on bedform dynamics in terms of the growth, decay, and speed of ripples. Finally, we examine the defect-free interactions in the later stages of bed evolution, which primarily lead to wave coarsening. Key Points Isolated ripples maintain a self-similar shape and bed shear stress profiles Bedform-bedform interactions can significantly modify bedform celerity Spectra of bed height variation suggest a Reynolds number dependenc

Direct Numerical Simulation of Transverse Ripples: 1. Pattern Initiation and Bedform Interactions

We present results of coupled direct numerical simulations between flow and a deformable bed in a horizontally periodic, turbulent open channel at a shear Reynolds number of Reτ = 180. The feedback between the temporally and spatially evolving bed and the flow is enforced via the immersed boundary method. Using the near-bed flow field, we provide evidence on the role of locally intense near-bed vortical structures during the early stages of bed formation, from the emergence of quasi-streamwise streaks to the formation of incipient bedform crestlines. Additionally, we take a new look at a number of defect-related bedform interactions, including lateral linking, defect and bedform repulsion, merging, and defect creation, and show that the underlying mechanisms, in these flow-aligned interactions, are very similar to each other. Consequently, the interactions are labeled differently depending on the geometry of interacting structures and the outcome of the interaction. In the companion paper, we compare our results to published experimental data and provide an extensive quantitative analysis of the bed, where we demonstrate the importance of neighboring structures, especially upstream neighbors, on bedform dynamics (growth/decay and speed) and wave coarsening. Video files of bed evolution are available in the supporting information. Key Points Mesoscale resolved simulations show the different mechanisms for bedform-bedform interactions to be very similar to each other Similar to laminar flows over dunes and ripples, a positive phase shift is observed between bed shear stress and topology even in mesoscale-resolved turbulent flow field Simulations match Coleman and Melville (1996) theory on bedform initiation from a flat be

Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications

Curcumin, a yellow polyphenolic pigment from the Curcuma longa L. (turmeric) rhizome, has been used for centuries for culinary and food coloring purposes, and as an ingredient for various medicinal preparations, widely used in Ayurveda and Chinese medicine. In recent decades, their biological activities have been extensively studied. Thus, this review aims to offer an in-depth discussion of curcumin applications for food and biotechnological industries, and on health promotion and disease prevention, with particular emphasis on its antioxidant, anti-inflammatory, neuroprotective, anticancer, hepatoprotective, and cardioprotective effects. Bioavailability, bioefficacy and safety features, side effects, and quality parameters of curcumin are also addressed. Finally, curcumin’s multidimensional applications, food attractiveness optimization, agro-industrial procedures to offset its instability and low bioavailability, health concerns, and upcoming strategies for clinical application are also covered

Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach

Endoxifen is the most important metabolite of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing breast cancer patients that do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at higher recurrence risk. In this investigation, 10 clinical tamoxifen studies were pooled (nPatients=1388) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modelling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared to post-menopausal patients, pre-menopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared to elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for pre-menopausal patients, this subpopulation may benefit most from individualised tamoxifen dosing

S-Glutathionylation at Cys328 and Cys542 Impairs STAT3 Phosphorylation.

STAT3 is a latent transcription factor that promotes cell survival and proliferation and is often constitutively active in cancers. Although many reports provide evidence that STAT3 is a direct target of oxidative stress, its redox regulation is poorly understood. Under oxidative conditions STAT3 activity can be modulated by S-glutathionylation, a reversible redox modification of cysteine residues. This suggests the possible cross-talk between phosphorylation and glutathionylation and points out that STAT3 is susceptible to redox regulation. Recently, we reported that decreasing the GSH content in different cell lines induces inhibition of STAT3 activity through the reversible oxidation of thiol groups. In the present work, we demonstrate that GSH/diamide treatment induces S-glutathionylation of STAT3 in the recombinant purified form. This effect was completely reversed by treatment with the reducing agent dithiothreitol, indicating that S-glutathionylation of STAT3 was related to formation of protein-mixed disulfides. Moreover, addition of the bulky negatively charged GSH moiety impairs JAK2-mediated STAT3 phosphorylation, very likely interfering with tyrosine accessibility and thus affecting protein structure and function. Mass mapping analysis identifies two glutathionylated cysteine residues, Cys328 and Cys542, within the DNA-binding domain and the linker domain, respectively. Site direct mutagenesis and in vitro kinase assay confirm the importance of both cysteine residues in the complex redox regulatory mechanism of STAT3. Cells expressing mutant were resistant in this regard. The data presented herein confirmed the occurrence of a redox-dependent regulation of STAT3, identified the more redox-sensitive cysteines within STAT3 structure, and may have important implications for development of new drugs

Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R2: 53%, P<10?77). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P=0.013). Low (<14?nM) compared with high (>35?nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS

Changes in circulating microRNA levels can be identified as early as day 8 of pregnancy in cattle

<div><p>Poor reproductive performance remains a major issue in the dairy industry, with low conception rates having a significant impact on milk production through extended calving intervals. A major limiting factor is the lack of reliable methods for early pregnancy diagnosis. Identification of animals within a herd that fail to conceive within 3 weeks after insemination would allow early re-insemination and shorten calving intervals. In a previous study, we found an increase in plasma miR-26a levels in Day 16-pregnant relative to non-pregnant heifers, however changes in miRNA levels that early during pregnancy were very small which likely prevented the identification of robust biomarkers. In this study, we extended our analyses to a wider interval during pregnancy (Days 8 to 60, n = 11 heifers) with the rationale that this may facilitate the identification of additional early pregnancy miRNA biomarkers. Using small RNA sequencing we identified a total of 77 miRNAs that were differentially expressed on Day 60 relative to Day 0 of pregnancy. We selected 14 miRNAs for validation by RT-qPCR and confirmed significant differences in the expression of let-7f, let-7c, miR-30c, miR-101, miR-26a, miR-205 and miR-143 between Days 0 and 60. RT-qPCR profiling throughout Days 0, 8, 16 and 60 of pregnancy showed a distinct increase in circulating levels of miR-26a (3.1-fold, P = 0.046) as early as Day 8 of pregnancy. In summary, in contrast to earlier stages of pregnancy (≤ Day 24), marked differences in the levels of multiple miRNAs can be detected in circulation by Day 60 in cattle. Retrospective analyses showed miR-26a levels to be increased in circulation as early as Day 8, sooner than previously reported in any species, suggesting a biological role for this miRNA in the very early events of pregnancy.</p></div

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy