Summary
Background Functional gut symptoms are induced by inclusion and reduced by dietary restriction of poorly absorbed short‐chain carbohydrates (FODMAPs), but the mechanisms of action remain ...untested.
Aims To determine the effect of dietary FODMAPs on the content of water and fermentable substrates of ileal effluent.
Methods Twelve ileostomates without evidence of small intestinal disease undertook two 4‐day dietary periods, comprising diets differing only in FODMAP content in a randomized, cross‐over, single‐blinded intervention study. Daytime (14 h) ileal effluent was collected on day four of each diet. Patients rated effluent volume and consistency on a 10‐cm visual analogue scale. The FODMAP content of the diet and effluent was measured.
Results Ingested FODMAPs of 32% (range 6–73%) was recovered in the high FODMAP diet effluent. Effluent collection weight increased by a mean of 22% (95% CI, 5–39), water content by 20% (2–38%) and dry weight by 24% (4–43%) with the high compared to low FODMAP diet arm. Output increased by 95 (28–161) mL. Volunteers perceived effluent consistency was thicker (95% CI, 0.6–1.9) with the low FODMAP diet than with the high FODMAP diet (3.5–6.1; P = 0.006).
Conclusions These data support the hypothetical mechanism; FODMAPs increase delivery of water and fermentable substrates to the proximal colon.
Summary
Background Fructose malabsorption, lactose malabsorption and an early rise in breath hydrogen after lactulose (ERBHAL) may play roles in induction of symptoms in gastrointestinal conditions.
...Aim To compare prevalence and interactions of fructose malabsorption, lactose malabsorption and ERBHAL among healthy subjects and those with chronic intestinal disorders using consistent breath hydrogen testing methodologies.
Methods Consecutive series of Caucasian patients with Crohn’s disease (n = 91), ulcerative colitis (56), functional gastrointestinal disorders (FGID) (201), coeliac disease (136) and 71 healthy volunteers underwent breath hydrogen testing using lactulose, fructose and lactose.
Results Early rise in breath hydrogen after lactulose occurred more commonly in healthy controls (39%) than in Crohn’s disease (20%) and untreated coeliac disease (14%; P < 0.008), but not FGID (27%), ulcerative colitis (26%) or treated coeliac disease (29%). Fructose malabsorption was more frequent in Crohn’s disease (61%) than other groups (33–44%, P < 0.05). Lactose malabsorption was most common in Crohn’s disease (42%) and ulcerative colitis (40%) and uncommon (10%) in 79 patients with newly diagnosed coeliac disease. In Crohn’s disease, concurrent Fructose malabsorption and lactose malabsorption was most common (29%), and the association of fructose malabsorption with ERBHAL seen overall (62%) was not observed (36%, P < 0.0001).
Conclusions Carbohydrate malabsorption and ERBHAL are normal physiological phenomena. The abnormal patterns observed in Crohn’s disease may have pathogenic importance.
Summary
Fructose is found widely in the diet as a free hexose, as the disaccharide, sucrose and in a polymerized form (fructans). Free fructose has limited absorption in the small intestine, with up ...to one half of the population unable to completely absorb a load of 25 g. Average daily intake of fructose varies from 11 to 54 g around the world. Fructans are not hydrolysed or absorbed in the small intestine.
The physiological consequences of their malabsorption include increasing osmotic load, providing substrate for rapid bacterial fermentation, changing gastrointestinal motility, promoting mucosal biofilm and altering the profile of bacteria. These effects are additive with other short‐chain poorly absorbed carbohydrates such as sorbitol.
The clinical significance of these events depends upon the response of the bowel to such changes; they have a higher chance of inducing symptoms in patients with functional gut disorders than asymptomatic subjects. Restricting dietary intake of free fructose and/or fructans may have durable symptomatic benefits in a high proportion of patients with functional gut disorders, but high quality evidence is lacking.
It is proposed that confusion over the clinical relevance of fructose malabsorption may be reduced by regarding it not as an abnormality but as a physiological process offering an opportunity to improve functional gastrointestinal symptoms by dietary change.
Background
Life‐long gluten‐free diet (GFD) is the only recognised treatment for coeliac disease (CD). The present study aimed to determine the nutritional adequacy of the ‘no detectable gluten’ ...diet.
Methods
Seven‐day prospective food intake was assessed in 55 patients who were adherent to a GFD for more than 2 years and in 50 newly‐diagnosed age‐ and sex‐matched patients (18–71 years, 24% male) studied prospectively over 12 months on GFD. Historical precoeliac intake was also assessed in the latter group. Intake was compared with Australian Nutritional Recommendations and the Australian population data.
Results
Nutritional intake was similar between groups. Of macronutrients, only starch intake fell over 12 months (26% to 23%, P = 0.04). Fibre intake was inadequate for all except in diet‐experienced men. More than one in 10 of both newly‐diagnosed and experienced women had inadequate thiamin, folate, vitamin A, magnesium, calcium and iron intakes. More than one in 10 newly‐diagnosed men had inadequate thiamin, folate, magnesium, calcium and zinc intakes. Inadequate intake did not relate to nutrient density of the GFD. Inadequacies of folate, calcium, iron and zinc occurred more frequently than in the Australian population. The frequency of inadequacies was similar pre‐ and post‐diagnosis, except for thiamin and vitamin A, where inadequacies were more common after GFD implementation.
Conclusions
Dietary intake patterns at 12 months on a GFD are similar to longer‐term intake. Dietary inadequacies are common and may relate to habitual poor food choices in addition to inherent deficiencies in the GFD. Dietary education should also address the achievement of adequate micronutrient intake. Fortification of GF foods also need to be considered.
The density matrix quantum Monte Carlo (DMQMC) method is used to sample exact-on-average N-body density matrices for uniform electron gas systems of up to 10^{124} matrix elements via a stochastic ...solution of the Bloch equation. The results of these calculations resolve a current debate over the accuracy of the data used to parametrize finite-temperature density functionals. Exchange-correlation energies calculated using the real-space restricted path-integral formalism and the k-space configuration path-integral formalism disagree by up to ∼10% at certain reduced temperatures T/T_{F}≤0.5 and densities r_{s}≤1. Our calculations confirm the accuracy of the configuration path-integral Monte Carlo results available at high density and bridge the gap to lower densities, providing trustworthy data in the regime typical of planetary interiors and solids subject to laser irradiation. We demonstrate that the DMQMC method can calculate free energies directly and present exact free energies for T/T_{F}≥1 and r_{s}≤2.
Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) ...has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)-the Pfizer-BioNTech mRNA COVID-19 vaccine-in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit-risk profile remains strongly in favor of COVID-19 vaccination in this population.
Summary
Susceptibility to the development of Crohn's disease involves a combination of genetic and environmental factors. The association of Crohn's disease with westernization has implicated ...lifestyle factors in pathogenesis. While diet is a likely candidate, evidence for specific changes in dietary habits and/or intake has been lacking.
A new hypothesis is proposed, by which excessive delivery of highly fermentable but poorly absorbed short‐chain carbohydrates and polyols (designated FODMAPs – Fermentable Oligo‐, Di‐ and Mono‐saccharides And Polyols) to the distal small intestinal and colonic lumen is a dietary factor underlying susceptibility to Crohn's disease. The subsequent rapid fermentation of FODMAPs in the distal small and proximal large intestine induces conditions in the bowel that lead to increased intestinal permeability, a predisposing factor to the development of Crohn's disease. Evidence supporting this hypothesis includes the increasing intake of FODMAPs in western societies, the association of increased intake of sugars in the development of Crohn's disease, and the previously documented effects of the ingestion of excessive FODMAPs on the bowel. This hypothesis provides potential for the design of preventive strategies and raises concern about current enthusiasm for putative health‐promoting effects of FODMAPs.
One of the greatest challenges in defining the pathogenesis of Crohn's disease is to identify predisposing environmental factors. Such an achievement might lead to the development of preventive strategies for, and the definition of, possible target for changing the natural history of this serious disease. The present paper describes a new hypothesis for one such environmental factor.
ABSTRACT
Using full disc synoptic maps of solar background magnetic field captured from the Wilcox Solar Observatory for 30 latitudinal bands for cycles 21–24, principal components (PCs) or ...eigenvectors of magnetic oscillations are obtained. The PCs are shown to come in pairs assigned to magnetic waves produced by dipole, quadruple, sextuple, and octuple magnetic sources. The first pair is linked to dipole magnetic waves with their summary curve revealing a reasonable fit to the averaged sunspot numbers in cycles 21–24. This verifies the previous results and confirms the summary curve as additional proxy of solar activity decreasing towards grand solar minimum in cycles 25–27. There is also a noticeable asymmetry in latitudinal distributions of these PCs showing an increased activity in Northern hemisphere in odd cycles and in Southern hemisphere in even ones similar to the N–S asymmetries observed in sunspots. The second pair of PCs linked to quadruple magnetic sources has 50${{\ \rm per\ cent}}$ smaller amplitudes than the first, while their summary curve correlates closely with soft X-ray fluxes in solar flares. Flare occurrences are also linked to variations of the next two pairs of eigenvectors, quadruple and sextuple components, revealing additional periodicity of about 2.75–3.1 yr similar to observed oscillations in flares. Strong latitudinal asymmetries in quadruple and sextuple components are correlating with the N–S asymmetries of flare occurrences skewed to Southern hemisphere in even cycles and to Northern hemisphere in odd ones. Principal component analysis of solar magnetic field raises perspectives for simultaneous prediction of general and flaring solar activity.
Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent ...poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer.
Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1:1:1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR).
Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively hazard ratio (HR) 0.789; 95% CI 0.536–1.162; P = 0.227, interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503–1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278–2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032–2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP.
Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population.
NCT01506609
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