Vitamin D associates with improved quality of life in participants with irritable bowel syndrome: outcomes from a pilot trial

Background: Vitamin D deficiency has been associated or implicated with the pathophysiology of the gastrointestinal conditions inflammatory bowel disease and colorectal cancer, as well as with depression. No trials or epidemiology studies to date have investigated a link with irritable bowel syndrome (IBS). A single case report has suggested a benefit in IBS of vitamin D supplementation. We hypothesised that IBS participants with vitamin D insufficiency would benefit from repletion in terms of their IBS symptoms. We undertook a pilot trial to provide data to support a power calculation and to justify a full trial. Methods: This was a randomised, double blinded, three-arm parallel design trial of vitamin D, placebo or a combination of vitamin D and probiotics. Participants were further stratified according to whether they were vitamin D replete or insufficient. Vitamin D status was determined by blood test at baseline and exit; IBS symptoms were assessed by validated questionnaire; dietary intakes were assessed by food frequency questionnaire. Results: A significant proportion of the IBS population were vitamin D deficient, such that the replete stratum could not be adequately recruited. There was a significant association in the baseline data between circulating vitamin D level and quality of life (“How much has IBS affected your life?”). Supplementation significantly improved vitamin D level versus placebo. IBS symptoms were not significantly improved in this pilot, although a power calculation was enabled from the intervention data. Conclusions: The IBS population exhibits significant levels of vitamin D insufficiency and would benefit from screening and possible supplementation. The impact of IBS on quality of life may be reduced by vitamin D level. Future trials should have a sample size of over 9

Relationship between immune checkpoint proteins, tumour microenvironment characteristics, and prognosis in primary operable colorectal cancer

The tumour microenvironment is an important factor for colorectal cancer prognosis, affecting the patient's immune response. Immune checkpoints, which regulate the immune functions of lymphocytes, may provide prognostic power. This study aimed to investigate the prognostic value of the immune checkpoints TIM‐3, LAG‐3 and PD‐1 in patients with stage I–III colorectal cancer. Immunohistochemistry was employed to detect TIM‐3, LAG‐3, PD‐1 and PD‐L1 in 773 patients with stage I–III colorectal cancer. Immune checkpoint protein expression was assessed in tumour cells using the weighted histoscore, and in immune cells within the stroma using point counting. Scores were analysed for associations with survival and clinical factors. High tumoural LAG‐3 (hazard ratio [HR] 1.45 95% confidence interval [CI] 1.00–2.09, p = 0.049) and PD‐1 (HR 1.34 95% CI 1.00–1.78, p = 0.047) associated with poor survival, whereas high TIM‐3 (HR 0.60 95% CI 0.42–0.84, p = 0.003), LAG‐3 (HR 0.58 95% CI 0.40–0.87, p = 0.006) and PD‐1 (HR 0.65 95% CI 0.49–0.86, p = 0.002) on immune cells within the stroma associated with improved survival, while PD‐L1 in the tumour (p = 0.487) or the immune cells within the stroma (p = 0.298) was not associated with survival. Furthermore, immune cell LAG‐3 was independently associated with survival (p = 0.017). Checkpoint expression scores on stromal immune cells were combined into a Combined Immune Checkpoint Stromal Score (CICSS), where CICSS 3 denoted all high, CICSS 2 denoted any two high, and CICSS 1 denoted other combinations. CICSS 3 was associated with improved patient survival (HR 0.57 95% CI 0.42–0.78, p = 0.001). The results suggest that individual and combined high expression of TIM‐3, LAG‐3, and PD‐1 on stromal immune cells are associated with better colorectal cancer prognosis, suggesting there is added value to investigating multiple immune checkpoints simultaneously

Analysis of LIGO data for gravitational waves from binary neutron stars

We report on a search for gravitational waves from coalescing compact binary systems in the Milky Way and the Magellanic Clouds. The analysis uses data taken by two of the three LIGO interferometers during the first LIGO science run and illustrates a method of setting upper limits on inspiral event rates using interferometer data. The analysis pipeline is described with particular attention to data selection and coincidence between the two interferometers. We establish an observational upper limit of $\mathcal{R}<$1.7 \times 10^{2}$per year per Milky Way Equivalent Galaxy (MWEG), with 90coalescence rate of binary systems in which each component has a mass in the range 1--3$M_\odot$.Comment: 17 pages, 9 figure

Production of singlet P-wave ccˉc \bar c and bbˉb \bar b states

No spin-singlet $b \bar b$ quarkonium state has yet been observed. In this paper we discuss the production of the singlet P-wave $b\bar{b}$ and $c\bar{c}$ $^1P_1$ states $h_b$ and $h_c$. We consider two possibilities. In the first the $^1P_1$ states are produced via the electromagnetic cascades \ups(3S) \to \eta_b(2S) + \gamma \to h_b + \gamma \gamma \to \eta_b +\gamma\gamma\gamma and $\psi'\to \eta_c' + \gamma \to h_c + \gamma \gamma \to \eta_c + \gamma\gamma\gamma$. A more promising process consists of single pion transition to the $^1P_1$ state followed by the radiative transition to the $1^1S_0$ state: \ups(3S)\to h_b + \pi^0 \to \eta_b + \pi^0 +\gamma and $\psi' \to h_c + \pi^0 \to \eta_c + \pi^0 +\gamma$. For a million \ups(3S) or $\psi'$'s produced we expect these processes to produce several hundred events.Comment: 13 pages, LaTeX, 1 figure, to be published Phys. Rev. D. Some equation numbers and one table number correcte

Dynamical Left-Right Symmetry Breaking

We study a left--right symmetric model which contains only elementary gauge boson and fermion fields and no scalars. The phenomenologically required symmetry breaking emerges dynamically leading to a composite Higgs sector with a renormalizable effective Lagrangian. We discuss the pattern of symmetry breaking and phenomenological consequences of this scenario. It is shown that a viable top quark mass can be achieved for the ratio of the VEVs of the bi--doublet $\tan\beta\equiv\kappa/\kappa'$ =~ 1.3--4. For a theoretically plausible choice of the parameters the right--handed scale can be as low as $\sim 20 TeV$; in this case one expects several intermediate and low--scale scalars in addition to the \SM Higgs boson. These may lead to observable lepton flavour violation effects including $\mu\to e\gamma$ decay with the rate close to its present experimental upper bound.Comment: 51 pages, LaTeX and uuencoded, packed Postscript figures. The complete paper, including figures, is also available via WWW at http://www.cip.physik.tu-muenchen.de/tumphy/d/T30d/PAPERS/ TUM-HEP-222-95.ps.g

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes