The genome of
, the bacterium responsible for the disease tuberculosis, contains an unusual family of abundant antigens (PE/PPEs). To date, certain members of this multigene family occur only in ...mycobacteria that cause disease. It is possible that the numerous proteins encoded by these mycobacterial genes dictate the immune pathogenesis of this bacterial pathogen. There is also evidence that some of these antigens are present at the cell surface and that they affect the pathology and immunology of the organism in many ways. Also, they elicit both antibodies and T cells, they may be involved in antigenic variation, and they may be good candidates for vaccines and drugs. However, since they are plentiful and extremely homologous, these PE/PPEs are very challenging to study, and it is difficult to be certain what role(s) they have in the pathogenesis of tuberculosis. Consequently, how to develop treatments like vaccines using these antigens as candidates is complex.
Abstract Opioids are an established option in the analgesic armamentarium for managing moderate-to-severe chronic pain. Long-term opioid use, however, is associated with several potential adverse ...effects and toxicities, such as peripheral edema, immune suppression, hyperalgesia, sleep apnea, and changes in endocrine function, many of which are not fully appreciated. Opioid endocrinopathy can greatly affect patients, causing reduced sexual function, decreased libido, infertility, mood disorders, osteoporosis, and osteopenia. Furthermore, although opioid endocrinopathy appears to be common, many patients do not report their symptoms, thus causing this adverse effect to go unnoticed and without clinical monitoring, particularly in patients chronically taking the equivalent of ≥100 mg of morphine daily. Indeed, diagnosing hypogonadism as opioid-related can be challenged by other influences on endocrine function, such as pain pathophysiology, comorbidities, other drug therapies, and patient age. Management options for opioid endocrinopathy include discontinuing opioid therapy, reducing the opioid dose, switching to a different opioid, and hormone supplementation.
Starch is the major stored carbohydrate in grains and legumes. Apart from nutritional functionality, starch has multiple industrial applications. Starch is synthesised in plant cells along with ...proteins, lipids, and polyphenols. These macromolecules interact both in planta as well as during downstream processing, e.g., extraction of starch.
Whilst the interaction of starch with protein, lipids, and other hydrocolloids during processing is widely reported, the in planta interactions and their effect on food and nutritional functionality is mostly overlooked. This review provides an overview of mechanisms of interaction of starch with protein, lipids, and polyphenols in planta and the effect of these interactions on food processing as well as human nutrition.
The interaction of starch with other macronutrients as well as polyphenols are described at the granular level as well as at the cellular level and presented in a schematic model (Fig. 1). The granular level interactions such as with surface and internal protein and lipids associated with granules, extra-granular storage proteins and formation of amylose-lipid and polyphenol complexes primarily affect the processing functionality of starch, whereas cellular level interactions and encapsulation enhance nutritional functionality of starch in terms of lowering the metabolic responses from energy dense nutrients. Thus, consideration of in planta interactions among macronutrients as well as with cell walls is important during processing, in both selection of ingredients as well as the formulation of foods.
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•Starch interacts with proteins, lipids, phytochemicals and cell walls in planta.•In planta interactions affect the functional and nutritional properties of starch.•Intact cellular structures conserve interactions and nutritional functionality.
Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on ...cardiovascular outcomes remain uncertain.
We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.
A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients 11.7% vs. 927 13.3%; hazard ratio, 0.87; 95% confidence interval CI, 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 8.2% vs. 663 9.5%; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 3.7% vs. 334 4.8%; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 6.2% vs. 529 7.6%; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels.
Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).
Trace organic contaminants (TrOCs) often pass through conventional activated sludge wastewater treatment plants (CAS-WWTPs) and are discharged into surface waters, where they can threaten aquatic ...ecosystems and human health, largely due to the hormone disrupting effects of certain TrOCs. The integrated fixed-film activated sludge (IFAS) process is a cost-effective means of upgrading CAS-WWTPs by adding free-floating carrier media, which promotes biofilm formation in the well-mixed suspended growth reactors, providing a potential niche for slow-growing microorganisms. Although IFAS upgrades are typically aimed at enhancing nutrient removal, limited bench- and pilot-scale data indicate that TrOC removal may also be improved. However, only limited reports which focus on a small number of compounds in individual full-scale IFAS-WWTPs have been published to date, and no data is available regarding the removal of estrogenic activity in full-scale IFAS-WWTPs. In this study, six full-scale IFAS-WWTPs were surveyed to quantify TrOC and estrogenic activity removal. Twenty-four hour composite samples of secondary influent and effluent (pre-disinfection) were analyzed for total suspended solids (TSS), chemical oxygen demand (COD), ammonia, total nitrogen (TN), total phosphorus (TP), estrogenic activity, and 98 TrOCs. The biomass distribution between the suspended growth phase (i.e. mixed liquor) and IFAS media was also assessed. All IFAS-WWTPs performed well in terms of TSS, COD, and ammonia removal. TN removal varied in accordance with nitrate removal. Total solids per liter of wetted reactor volume ranged from 2.5 to 7.6 g, with 40–60% attached to media. TrOCs with no detection (17) and those with high median removal (23, ≥90% average removal) were observed. Other TrOCs had lower and more variable removal efficiencies. Qualitative comparison with CAS literature shows potentially higher IFAS removal efficiencies for a number of compounds including several which have been previously indicated in bench- or pilot-scale studies (atenolol, diclofenac, gemfibrozil, DEET, 4-nonylphenol, and 4-tert-octylphenol), as well as the chlorinated flame retardants TCIPP and TDCIPP. Effluent estrogenic activity was found to be similar to that reported for full-scale CAS-WWTPs. These results provide the first survey of multiple full-scale IFAS-WWTPs employing mobile plastic carrier media in terms of basic chemical endpoints (removal of ammonia, TN, TP, and COD), the distribution of solids within the systems, and the removal of TrOCs and estrogenic activity.
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•First survey of trace organic contaminant removal in multiple full-scale IFAS-WWTPs.•Consistent with bench and pilot studies, removal of some TrOCs enhanced with IFAS.•Potentially enhanced removal of chlorinated flame retardants TCIPP and TDCIPP.•Significant removal of estrogenic activity corresponds with contaminant removal.
Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects ...remains unknown. Here, we devise a platform for functional profiling of DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with HGSC for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic.
Patient-derived ovarian tumor organoids grow rapidly and match the tumors from which they are derived, both genetically and functionally. These organoids can be used for DNA repair profiling and therapeutic sensitivity testing and provide a rapid means of assessing targetable defects in the parent tumor, offering more suitable treatment options.
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Introducing new medical devices into routine practice raises concerns because patients and outcomes may differ from those in randomized trials.
To update the previous report of 30-day outcomes and ...present 1-year outcomes following transcatheter aortic valve replacement (TAVR) in the United States.
Data from the Society of Thoracic Surgeons/American College of Cardiology (STS/ACC) Transcatheter Valve Therapies Registry were linked with patient-specific Centers for Medicare & Medicaid Services (CMS) administrative claims data. At 299 US hospitals, 12 182 patients linked with CMS data underwent TAVR procedures performed from November 2011 through June 30, 2013, and the end of the follow-up period was June 30, 2014.
Transcatheter aortic valve replacement.
One-year outcomes including mortality, stroke, and rehospitalization were evaluated using multivariate modeling.
The median age of patients was 84 years and 52% were women, with a median STS Predicted Risk of Operative Mortality (STS PROM) score of 7.1%. Following the TAVR procedure, 59.8% were discharged to home and the 30-day mortality was 7.0% (95% CI, 6.5%-7.4%) (n = 847 deaths). In the first year after TAVR, patients were alive and out of the hospital for a median of 353 days (interquartile range, 312-359 days); 24.4% (n = 2074) of survivors were rehospitalized once and 12.5% (n = 1525) were rehospitalized twice. By 1 year, the overall mortality rate was 23.7% (95% CI, 22.8%-24.5%) (n = 2450 deaths), the stroke rate was 4.1% (95% CI, 3.7%-4.5%) (n = 455 stroke events), and the rate of the composite outcome of mortality and stroke was 26.0% (25.1%-26.8%) (n = 2719 events). Characteristics significantly associated with 1-year mortality included advanced age (hazard ratio HR for ≥95 vs <75 years, 1.61 95% CI, 1.24-2.09; HR for 85-94 years vs <75 years, 1.35 95% CI, 1.18-1.55; and HR for 75-84 years vs <75 years, 1.23 95% CI, 1.08-1.41), male sex (HR, 1.21; 95% CI, 1.12-1.31), end-stage renal disease (HR, 1.66; 95% CI, 1.41-1.95), severe chronic obstructive pulmonary disease (HR, 1.39; 95% CI, 1.25-1.55), nontransfemoral access (HR, 1.37; 95% CI, 1.27-1.48), STS PROM score greater than 15% vs less than 8% (HR, 1.82; 95% CI, 1.60-2.06), and preoperative atrial fibrillation/flutter (HR, 1.37; 95% CI, 1.27-1.48). Compared with men, women had a higher risk of stroke (HR, 1.40; 95% CI, 1.15-1.71).
Among patients undergoing TAVR in US clinical practice, at 1-year follow-up, overall mortality was 23.7%, the stroke rate was 4.1%, and the rate of the composite outcome of death and stroke was 26.0%. These findings should be helpful in discussions with patients undergoing TAVR.
The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The ...significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein–protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure–activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.
Background: It has been suggested that metabolomics could play a role in dietary assessment and identification of novel biomarkers of dietary intake.
Objective: This study examined the link between ...habitual dietary patterns and metabolomic profiles.
Design: A total of 160 volunteers participated in a double-blind, randomized, placebo-controlled dietary intervention. We collected biofluids and recorded 3-d food diaries. Food data were reduced to 33 food groups, and a k-means cluster analysis was performed to identify dietary patterns. 1H Nuclear magnetic resonance (NMR) spectra were acquired for plasma and urine samples, and gas chromatography was used for plasma fatty acid profiling.
Results: Cluster analysis identified 3 distinct dietary patterns on the basis of the energy contribution of different food groups. Dietary clusters were reflected in plasma fatty acid profiles and in metabolomic data. 1H NMR spectra of urine allowed the identification of metabolites associated with different dietary patterns. Several of the metabolites identified were linked to the intake of specific food groups; in particular, there was a positive association between O-acetylcarnitine and phenylacetylglutamine and red-meat and vegetable intakes, respectively.
Conclusions: Habitual dietary patterns are shown in metabolomic data. This approach successfully identified potential biomarkers of red-meat and vegetable intakes.
Transcatheter aortic valve replacement (TAVR) was approved by the US Food and Drug Administration for the treatment of severe, symptomatic aortic stenosis and inoperable status (in 2011) and ...high-risk but operable status (starting in 2012). A national registry (the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy STS/ACC TVT Registry) was initiated to meet a condition for Medicare coverage and also facilitates outcome assessment and comparison with other trials and international registries.
To report the initial US commercial experience with TAVR.
We obtained results from all eligible US TAVR cases (n=7710) from 224 participating registry hospitals following the Edwards Sapien XT device commercialization (November 2011-May 2013).
Primary outcomes included all-cause in-hospital mortality and stroke following TAVR. Secondary analyses included procedural complications and outcomes by clinical indication and access site. Device implantation success was defined as successful vascular access, deployment of a single device in the proper anatomic position, appropriate valve function without either moderate or severe AR, and successful retrieval of the delivery system. Thirty-day outcomes are presented for a representative 3133 cases (40.6%) at 114 centers with at least 80% complete follow-up reporting.
The 7710 patients who underwent TAVR included 1559 (20%) cases that were inoperable and 6151 (80%) cases that were high-risk but operable. The median age was 84 years (interquartile range IQR, 78-88 years); 3783 patients (49%) were women and the median STS predicted risk of mortality was 7% (IQR, 5%-11%). At baseline, 2176 patients (75%) were either not at all satisfied (1297 patients 45%) or mostly dissatisfied (879 patients 30%) with their symptom status; 2198 (72%) had a 5-m walk time longer than 6 seconds (slow gait speed). The most common vascular access approach was transfemoral (4972 patients 64%), followed by transapical (2197 patients 29%) and other alternative approaches (536 patients 7%); successful device implantation occurred in 7069 patients (92%; 95% CI, 91%-92%). The observed incidence of in-hospital mortality was 5.5% (95% CI, 5.0%-6.1%). Other major complications included stroke (2.0%; 95% CI, 1.7%-2.4%), dialysis-dependent renal failure (1.9%; 95% CI, 1.6%-2.2%), and major vascular injury (6.4%; 95% CI, 5.8%-6.9%). Median hospital stay was 6 days (IQR, 4-10 days), with 4613 (63%) discharged home. Among patients with available follow-up at 30 days (n=3133), the incidence of mortality was 7.6% (95% CI, 6.7%-8.6%) (noncardiovascular cause, 52%); a stroke had occurred in 2.8% (95% CI, 2.3%-3.5%), new dialysis in 2.5% (95% CI, 2.0%-3.1%), and reintervention in 0.5% (95% CI, 0.3%-0.8%).
Among patients undergoing TAVR at US centers in the STS/ACC TVT Registry, device implantation success was achieved in 92% of cases, the overall in-hospital mortality rate was 5.5%, and the stroke rate was 2.0%. Although these postmarket US approval findings are comparable with prior published trial data and international experience, long-term follow-up is essential to assess continued efficacy and safety.
clinicaltrials.gov Identifier: NCT01737528.
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