Prebiotic Galacto-Oligosaccharides Impact Stool Frequency and Fecal Microbiota in Self-Reported Constipated Adults: A Randomized Clinical Trial

Constipation is a major issue for 10–20% of the global population. In a double-blind randomized placebo-controlled clinical trial, we aimed to determine a dose-response effect of galacto-oligosaccharides (GOS) on stool characteristics and fecal microbiota in 132 adults with self-reported constipation according to Rome IV criteria (including less than three bowel movements per week). Subjects (94% females, aged: 18–59 years) received either 11 g or 5.5 g of BiotisTM GOS, or a control product, once daily for three weeks. Validated questionnaires were conducted weekly to study primarily stool frequency and secondary stool consistency. At base- and endline, stool samples were taken to study fecal microbiota. A trend towards an increased stool frequency was observed after the intervention with 11 g of GOS compared to control. While during screening everybody was considered constipated, not all subjects (n = 78) had less than three bowel movements per week at baseline. In total, 11 g of GOS increased stool frequency compared to control in subjects with a low stool frequency at baseline (≤3 bowel movements per week) and in self-reported constipated adults 35 years of age or older. A clear dose-response of GOS was seen on fecal Bifidobacterium, and 11 g of GOS significantly increased Anaerostipes hadrus. In conclusion, GOS seems to be a solution to benefit adults with a low stool frequency and middle-aged adults with self-reported constipation.

Multiple Chemical Sensitivity

Multiple Chemical Sensitivity (MCS), a condition also known as Chemical Sensitivity (CS), Chemical Intolerance (CI), Idiopathic Environmental Illness (IEI) and Toxicant Induced Loss of Tolerance (TILT), is an acquired multifactorial syndrome characterized by a recurrent set of debilitating symptoms. The symptoms of this controversial disorder are reported to be induced by environmental chemicals at doses far below those usually harmful to most persons. They involve a large spectrum of organ systems and typically disappear when the environmental chemicals are removed. However, no clear link has emerged among self-reported MCS symptoms and widely accepted objective measures of physiological dysfunction, and no clear dose-response relationship between exposure and symptom reactions has been observed. In addition, the underlying etiology and pathogenic processes of the disorder remain unknown and disputed, although biologic and psychologic hypotheses abound. It is currently debated whether MCS should be considered a clinical entity at all. Nevertheless, in the last few decades MCS has received considerable scientific and governmental attention in light of the many persons reporting this illness. In this review, we provide a general overview of the history, definition, demographics, prevalence, and etiologic challenges in defining and understanding MCS.

Methylation risk scores for childhood aeroallergen sensitization: Results from the LISA birth cohort

Background It has been hypothesized that epigenomic modifications such as genomic methylation changes are an intermediate step linking environmental exposures with allergic disease development. Associations between individual DNA methylation CpG sites and allergic diseases have been reported, but they have not been assessed regarding their joint predictive capability. Methods Data were obtained from 240 children of the German LISA cohort. Blood-based DNA methylation was measured at six and ten years. Aeroallergen sensitization, at least RAST class 1, was measured in blood at six, ten and 15 years. We calculated six methylation risk scores (MRS) for allergy-related phenotypes based on available publications and assessed their performance both cross-sectionally and prospectively. Dose-response associations between aeroallergen sensitization and MRS, their correlation and mapping of common hits were evaluated. Results All six atopy-related MRS were highly correlated (r>0.86) and seven CpGs were included in more than one MRS. Cross-sectionally, we observed an 80% increased risk for aeroallergen sensitization at six years with an increased risk score by one standard deviation (best MRS: relative risk = 1.81, 95% confidence interval = [1.43; 2.27]). Significant associations were also seen at ten years and in prospective models, though the effect of the latter was attenuated when only including participants not sensitized at baseline. A clear dose-response relationship with RAST classes of aeroallergen sensitization could be established cross-sectionally, but not prospectively. Conclusion We found good classification and prediction capabilities of calculated allergy-related MRS, particularly cross-sectionally for the allergy prevalence, underlining the relevance of altered gene-regulation in allergic diseases.

Smoking Behavior and Prognosis After Colorectal Cancer Diagnosis: A Pooled Analysis of 11 Studies

Background Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies, but current evidence on smoking in association with survival after CRC diagnosis is limited. Methods We pooled data from 12,345 patients with stage I-IV CRC from 11 epidemiologic studies in the International Survival Analysis in Colorectal Cancer Consortium (ISACC). Cox proportional hazards regression models were used to evaluate the associations of pre-diagnostic smoking behavior with overall, CRC-specific and non-CRC-specific survival. Results Among 12,345 patients with CRC, 4379 (35.5%) died (2515 from CRC), over a median follow-up time of 7.5 years. Smoking was strongly associated with worse survival in stage I-III patients, whereas no association was observed among stage IV patients. Among stage I-III patients, clear dose-response relationships with all survival outcomes were seen for current smokers. For example, current smokers with ≥40 pack-years had statistically significantly worse overall, CRC-specific, and non-CRC-specific survival compared to never smokers (hazard ratio [HR] =1.94, 95% confidence interval [CI] =1.68–2.25; HR = 1.41, 95% CI = 1.12–1.78; and HR = 2.67, 95% CI = 2.19–3.26, respectively). Similar associations with all survival outcomes were observed for former smokers who had quit for less than 10 years, but only a weak association with non-CRC-specific survival was seen among former smokers who had quit for more than 10 years. Conclusions This large consortium of CRC patient studies provides compelling evidence that smoking is strongly associated with worse survival of stage I-III CRC patients in a clear dose-response manner. The detrimental effect of smoking was primarily related to non-colorectal cancer events, but current heavy smoking also showed an association with CRC-specific survival.

Tildacerfont in Adults with Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies

Context Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction. Objective Assess tildacerfont safety and efficacy. Design and Setting Two Phase 2 open-label studies. Patients Adults with 21OHD. Intervention Oral tildacerfont 200-1000 mg once daily (QD) (n=10) or 100-200 mg twice daily (n=9 and 7) for 2 weeks (Study 1) and 400 mg QD (n=11) for 12 weeks (Study 2). Main outcome measure Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤2x upper limit of normal (ULN) or A4 >2x ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results In Study 1, evaluable participants with baseline A4 >2x ULN (n=11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4 >2x ULN (n=5; 26-63 years, 40% female) had ~80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤2x ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%). Conclusions For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal.

Dietary Anti-Oxidant Capacity, Dietary Inflammation Index, and the Risk of Stroke in a Large Prospective Cohort Study.

BackgroundWhilst the Western and Mediterranean/prudent diets have long been associated with the risk of stroke, it is less clear if increased inflammation and reduction of oxidations are their respective mechanisms. This study aimed to understand the associations between the dietary inflammatory index (DII), and total anti-oxidant capacity of the diet (TAC), with regards to stroke risk.MethodsThe study population included 71,460 women free of cardiovascular disease at baseline from the E3N cohort, who completed a diet history questionnaire which was used to estimate the dietary pattern scores. Scores were considered grouped as quintiles and as splines in order to determine the dose-response shape. Hazard ratios (HRs) and 95% confidence intervals (95% CI) for hypertension were estimated with multivariate Cox models with age as the time scale, and adjusted for potential confounding factors. After Bonferroni correction, a p-value of 0.013 was considered significant.ResultsOver 14.5 years of follow-up, 414 cases of incident stroke were identified. The Western, and Prudent dietary patterns were both highly associated with the risk of stroke (Western HRQ1Q4 = 1.85 [1.27: 2.69], p-trend = 0.002, Prudent HRQ1Q4 = 0.59 [0.44: 0.78], p-trend < 0.001), as was TAC from non-coffee sources (HRQ1Q4 = 0.47 [0.33: 0.68], p-trend < 0.001). All three showed a clear dose-response, and the associations with the Western and Prudent scores were consistent in sensitivity analysis. Weaker evidence was observed for DII (HRQ1Q4 = 1.33 [1.01: 1.78], p-trend = 0.03), which did not show a clear dose-response. TAC from coffee was not associated with the risk of stroke.ConclusionThese results suggest that diets high in anti-oxidants are associated with a reduced risk of stroke, but that inflammation from the diet does not play as large a part in the risk of stroke. Factors other than inflammation may be driving associations with stroke and western diet.

Transportation container for pre-processing cytogenetic assays in radiation accidents

We report a shipping container that enables a disruptive logistics for cytogenetic biodosimetry for radiation countermeasures through pre-processing cell culture during transportation. The container showed precise temperature control (< 0.01 °C) with uniform sample temperature (< 0.1 °C) to meet the biodosimetry assay requirements. Using an existing insulated shipping box and long shelf life alkaline batteries makes it ideal for national stockpile. Dose curve of cytogenetic biodosimetry assay using the shipping container showed clear dose response and high linear correlation with the control dose curve using a laboratory incubator (Pearson’s correlation coefficient: 0.992). The container’s ability of pre-processing biological samples during transportation could have a significant impact on radiation countermeasure, as well as potential impacts in other applications such as biobanking, novel molecular or cell-based assays or therapies.

MO493PATTERNS OF HYPERKALEMIA AND ASSOCIATED ADVERSE HEALTH OUTCOMES IN PERSONS WITH CHRONIC KIDNEY DISEASE

Background and Aims Patients with CKD are often described as having chronic hyperkalemia, but earlier studies have relied on a single potassium measurement. Whether the hyperkalemia in CKD is chronic or transient, and whether temporal patterns have different outcome implications, is unknown. Method Observational study from the Stockholm Creatinine Measurements (SCREAM) project of patients with confirmed CKD G3-5. We extracted all data on potassium measured during routine outpatient care and estimated its longitudinal trajectories. At each month, we created a rolling assessment of the proportion of time in which potassium was abnormal during the previous year, defining patterns of normokalemia (100% of time with potassium 3.5-5.0 mmol/L), transient (&lt;50% of time with potassium &gt;5.0 mmol/L) and chronic hyperkalemia (≥50% of time with potassium &gt;5.0 mmol/L). We described the presence of chronic and transient hyperkalemia throughout the spectrum of CKD G3-5 and identified clinical predictors by logistic regression. Through time-dependent Cox models we examined whether previous hyperkalemia patterns offer prognostic gain beyond that of the current potassium value. Results We included 36,511 participants (56% women) with confirmed CKD G3-5, median age 81 years, and eGFR 46 ml/min/1.73 m2. During 3-year-median follow-up, patterns of transient and chronic hyperkalemia were observed in 15% and 4% of patients with CKD G3a, increasing to 50% and 17% of patients with CKD G5. Factors associated with chronic hyperkalemia were younger age, male sex, more severe CKD category, presence of diabetes or heart failure, use of renin-angiotensin system inhibitors, and use of potassium binders. Major cardiovascular events (MACE) occurred in 13,104 (36%) patients and 13,570 (37%) died. In time-dependent models, independent of identified confounders and of time-updated potassium values, compared with the normokalemic pattern, patients with transient (HR 1.37, 95% CI 1.29-1.46) or chronic (HR 1.17, 95% CI 1.04-1.32) hyperkalemia patterns were at higher risk of MACE. Transient hyperkalemia pattern (HR 1.43, 95% CI 1.35-1.52) and time-updated elevated potassium, but not a state of chronic hyperkalemia (HR 1.07, 95% CI 0.95-1.20), predicted the risk of death. Conclusion Chronic hyperkalemia occurs in 4-17% of patients with CKD G3-5. We did not observe a clear dose-response for the association between hyperkalemia pattern (normal, transient, chronic) with either MACE or death. There was modest incremental information in the previous potassium pattern, beyond potassium measured at a single time point.

Survival of the Sawfly Athalia rosae Upon Infection by an Entomopathogenic Fungus and in Relation to Clerodanoid Uptake

Larvae of the turnip sawfly Athalia rosae are a pest of Brassicacae plants, as their feeding can cause defoliation of various crops of economic importance. The larvae and the adults of this sawfly species are known to take up different classes of chemical compounds from their respective host plants, with potentially deterrent functions against predators. In addition, compounds taken up by the adults, the clerodanoids, are known for their antimicrobial activity. These features could be a challenge to biocontrol strategies. Several natural enemies of A. rosae have been identified, targeting larval and pupal stages of A. rosae, which could potentially be used as biocontrol agents. However, targeting the adult stage of a larval pest in addition to targeting the juvenile stages may improve population control. In this study, we ask whether a strain of the entomopathogenic fungus Beauveria bassiana shows biological activity against A. rosae adults. We also investigate whether the behavior of clerodanoid uptake by the adults, which is commonly found, affects their survival in response to a B. bassiana exposure. We found a clear dose-response relationship, i.e., with increasing fungal conidia concentrations survival of A. rosae decreased. However, there was only a low incidence of mycelial growth and sporulation from A. rosae cadavers, indicating that either the fungus is not successfully developing inside this host, or it is not able to re-emerge from it. Clerodanoid uptake decreased the survival of healthy adults; however, it did not increase their survival to B. bassiana. Our results revealed that this strain of B. bassiana if applied alone is probably not suitable for biocontrol of this sawfly species, because A. rosae showed a high baseline resistance against this fungus. The behavior of clerodanoid uptake is unlikely to have evolved as a defense against this entomopathogenic fungus.

Metal load and oxidative stress driven by organotin compounds on rainbow trout

Tributyltin-based (TBT) antifouling paints, widely used for the treatment of flooded surfaces, have been banned in 2008 for their high environmental persistence and bioaccumulation in aquatic organisms. Although it is still present in aquatic ecosystems, oxidative stress driven by TBT has been still poorly investigated in fish. The aim of the study was to examine the time-course stress responses in liver of rainbow trout that received a single intraperitoneal injection of tributyltin chloride (TBTC) or tributyltin ethoxide (TBTE), both at a dose of 0.05 and 0.5 mg/kg. Levels of metallothioneins, total glutathione, malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferase were evaluated at 3 and 6 days post-injection. Tin load was measured in the muscle of the same fish. Differences were observed in the time-course accumulation of tin with a clear dose-response relationship. Although individual oxidative stress biomarkers varied, the biomarker profile indicated different stress mechanisms caused by both TBTC and TBTE. The weak induction of metal-trapping metallothioneins and the changes of oxidative stress biomarkers suggested a stress-pressure in both TBT-treated trout, advising for an ecotoxicological risk for freshwater ecosystems.