Systematic review with meta-analysis: Safety and efficacy of local injections of mesenchymal stem cells in perianal fistulas

Perianal fistulas in Crohn's disease (CD) represent a highly debilitating and difficult-to-treat condition. Given emerging supportive evidence, we conducted a systematic review and meta-analysis of all trials/observational studies to establish the safety and efficacy of local injections of mesenchymal stem cells (MSCs). The PRISMA-P statement was applied for planning and reporting, and MEDLINE, EMBASE, Web of Science, Cochrane, CINAHL, ClinicalTrials.gov database, and ECCO 2017 proceedings were searched for published observational studies and one-arm and randomized clinical trials (RCTs). Safety was assessed in terms of acute local/systemic events, long-term events, and relatedness with MSC treatment. Efficacy was evaluated in terms of external and/or radiological closure of fistula tracks. After a review of 211 citations, 23 studies, including 696 participants, were evaluated. Four were RCTs with a total of 483 patients. Overall, fistula closure occurred in 80% of MSC-treated patients. In RCTs, this rate was 64% in the MSC arm and 37% in the control arm (relative risk (RR) = 1.54). Radiological response occurred in 83% of MSC-treated patients. Treatment-related adverse events occurred in 1% of MSC-treated patients, with severe treatment-related adverse events reaching 0% over a median follow-up of 6 months. In RCTs, treatment-related adverse events occurred in 13% in the MSC arm and 24% in the control arm (RR = 0.65). The relapse rate was 0. These results suggest that a local MSC injection is safe and efficacious. Further clinical trials with standardized end-points are required to ensure the timely implementation of this new therapy in the management of perianal CD

The Golden Strip of Correlated Top Quark, Gaugino, and Vectorlike Mass In No-Scale, No-Parameter F-SU(5)

We systematically establish the hyper-surface within the tan(beta), top quark mass m_t, universal gaugino mass M_1/2, and vectorlike mass M_V parameter volume which is compatible with the application of the No-Scale Supergravity boundary conditions, particularly the vanishing of the Higgs bilinear soft term B_mu, near to the Planck mass at the point M_F of ultimate F-lipped SU(5) unification. M_F is elevated from the penultimate partial unification near the traditional GUT scale at a mass M_32 by the inclusion of extra F-theory derived heavy vectorlike multiplets. We demonstrate that simultaneous adherence to all current experimental constraints, most importantly contributions to the muon anomalous magnetic moment (g-2)_mu, the branching ratio limit on (b \to s gamma), and the 7-year WMAP relic density measurement, dramatically reduces the allowed solutions to a highly non-trivial "golden strip" with tan(beta) \sim 15, m_t = 173.0-174.4 GeV, M_1/2 = 455-481 GeV, and M_V = 691-1020 GeV, effectively eliminating all extraneously tunable model parameters. We emphasize that the consonance of the theoretically viable m_t range with the experimentally established value is an independently correlated "postdiction". The predicted range of M_V is testable at the Large Hadron Collider (LHC). The partial lifetime for proton decay in the leading (e+|mu+) pi0 channels falls around 4.6 X 10^34 Y, testable at the future DUSEL and Hyper-Kamiokande facilities.Comment: V2, As accepted for publication in Physics Letters B; 7 pages, 3 figure

Pioglitazone and cause-specific risk of mortality in patients with type 2 diabetes: extended analysis from a European multidatabase cohort study.

OBJECTIVES: Describe and compare the risk of cardiovascular and non-cardiovascular mortality in patients whose antidiabetic therapy is modified to include pioglitazone compared with an alternative antidiabetic medication at the same stage of disease progression. RESEARCH DESIGN AND METHODS: This exploratory linked database cohort analysis used pooled health and mortality data from three European countries: Finland, Sweden and the UK. Propensity score together with exact matching was used to match 31 133 patients with type 2 diabetes first prescribed pioglitazone from 2000 to 2011, to 31 133 patients never prescribed pioglitazone. Exact matching variables were treatment stage, history of diabetes, diabetes complications and cardiovascular disease, and year of cohort entry. Mean follow-up time was 2.60 (SD 2.00) and 2.69 (SD 2.31) years in the pioglitazone and non-pioglitazone-exposed groups, respectively. Crude cause-specific mortality rates were ascertained. Association with pioglitazone use was estimated using Cox proportional hazards models adjusted a priori for country, age, sex, the propensity score quintile and time-dependent variables representing use of antidiabetic drugs. Stepwise testing identified no additional confounders to include in adjusted models. RESULTS: The crude mortality rate was lower in the pioglitazone-exposed group than the non-exposed group for both cardiovascular and non-cardiovascular mortality. Adjusted HRs comparing pioglitazone to alternative antidiabetic exposure were 0.58 (95% CI 0.52 to 0.63) and 0.63 (95% CI 0.58 to 0.68) for cardiovascular and non-cardiovascular mortality, respectively. A protective effect associated with pioglitazone was also found for all specific cardiovascular causes. CONCLUSIONS: This analysis suggests that pioglitazone is associated with a decrease in both cardiovascular and non-cardiovascular mortality. Results should be interpreted with caution due to the potential for residual confounding in this exploratory analysis. Further studies, specifically designed to test the association between pioglitazone use and patient-focused outcomes, are suggested. STUDY REGISTRATION NUMBER: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP; EUPAS3626)

On the Higgs Mass in the CMSSM

We estimate the mass of the lightest neutral Higgs boson h in the minimal supersymmetric extension of the Standard Model with universal soft supersymmetry-breaking masses (CMSSM), subject to the available accelerator and astrophysical constraints. For m_t = 174.3 GeV, we find that 114 GeV < m_h < 127 GeV and a peak in the tan beta distribution simeq 55. We observe two distinct peaks in the distribution of m_h values, corresponding to two different regions of the CMSSM parameter space. Values of m_h < 119 GeV correspond to small values of the gaugino mass m_{1/2} and the soft trilinear supersymmetry-breaking parameter A_0, lying along coannihilation strips, and most of the allowed parameter sets are consistent with a supersymmetric interpretation of the possibly discrepancy in g_mu - 2. On the other hand, values of m_h > 119 GeV may correspond to much larger values of m_{1/2} and A_0, lying in rapid-annihilation funnels. The favoured ranges of m_h vary with m_t, the two peaks being more clearly separated for m_t = 178 GeV and merging for m_t = 172.7 GeV. If the g_mu - 2 constraint is imposed, the mode of the m_h distribution is quite stable, being sim 117 GeV for all the studied values of m_t.Comment: 14 pages, 12 figure

Malignancy rates in Crohn's disease patients with perianal fistula: A German retrospective cohort study

BACKGROUND Patients with inflammatory bowel disease are at increased risk of colorectal and extra-intestinal cancer. However, the overall cancer risk in patients with Crohn's disease (CD) with perianal fistulas (PF) (CPF) and those with CD without PF (non-PF CD) is unclear. OBJECTIVE To describe the prevalence and incidence of cancer in patients with CPF and non-PF CD, and to estimate incidence rate ratio (IRR) of cancer between CPF and non-PF CD groups. METHODS A retrospective cohort study was conducted using the German InGef (Institute for Applied Health Research Berlin) research database. Patients with a CD record and PF from 1 January 2013 to 31 December 2014 were identified and followed up from 1 January 2015 until the first occurrence of cancer, end of health insurance contributing data, death, or end of study period (31 December 2020). Prevalence of any type of cancer including patients with CD diagnosed with cancer in the selection period and incidence of cancer excluding patients with CD diagnosed with cancer in the selection period were calculated. RESULTS In total, 10,208 patients with CD were identified. Of 824 patients with CPF (8.1%), 67 had had a malignancy (6-year period crude malignancy prevalence 8.13% [95% confidence interval (CI) 6.36%-10.21%]), which was lower than patients with non-PF CD (19.8% [95% CI 19%-20.6%]). Incidence (per 100,000 person-years) in patients with CPF was 1184 (95% CI 879-1561) and in non-PF CD was 2365 (95% CI 2219-2519). There was no significant difference in the adjusted IRR of cancer for the CPF group compared with the non-PF CD group (0.83 [95% CI 0.62-1.10]; p = 0.219). CONCLUSION There was no significant difference in the incidence of any cancer in patients with CPF compared with non-PF CD. However, patients with CPF had a higher numerical risk of cancer than the general German population

F-Theory Grand Unification at the Colliders

We predict the exact gaugino mass relation near the electroweak scale at one loop for gravity mediated supersymmetry breaking in F-theory SU(5) and SO(10) models with U(1)_Y and U(1)_{B-L} fluxes, respectively. The gaugino mass relation introduced here differs from the typical gaugino mass relations studied thus far, and in general, should be preserved quite well at low energy. Therefore, these F-Theory models can be tested at the Large Hadron Collider and future International Linear Collider. We present two typical scenarios that satisfy all the latest experimental constraints and are consistent with the CDMS II experiment. In particular, the gaugino mass relation is indeed satisfied at two-loop level with only a very small deviation around the electroweak scale.Comment: RevTex4, 6 pages, 6 figure

Prevalence of anal fistulas in Europe: Systematic literature reviews and population-based database analysis

Introduction: Despite the fact that perianal fistulas are associated with significant morbidity and impaired quality of life, their prevalence in Europe is unknown. The aim of this study was to estimate the prevalence of perianal fistulas in Europe, overall and according to etiology. Methods: Two independent literature reviews were performed using different search strategies to maximize the identification of potentially relevant studies. Data from relevant articles were used to estimate the prevalence of perianal fistulas in Europe. The robustness of the estimate was evaluated using data from a large population-based database from the UK. Results: A total of 26 studies provided epidemiological data on perianal fistulas, of which 16 provided suitable data to estimate the prevalence. Estimations using these data yielded a total prevalence of 1.69 per 10,000 population. Cryptoglandular infection and Crohn’s disease (CD) were the predominant etiologies, with prevalence rates at 0.86 and 0.76 per 10,000 population, respectively. Comparison of prevalence data from the UK population-based database with the European population resulted in a standardized prevalence estimate of all perianal fistulas of 1.83 per 10,000 population, confirming the robustness of the literaturebased estimate. Conclusion: Although in terms of incidence cryptoglandular fistulas were clearly predominant, the prevalence of fistulas in CD and cryptoglandular infection appeared more balanced. This is due to the longer duration and higher frequency of relapses of fistulas in CD. The estimated prevalence implies that perianal fistulas meet the criteria to be considered as a rare condition in Europe (prevalence less than 5 per 10,000 population).This study was funded by Takeda Pharmaceutical U.S.A., Inc. and TiGenix SA

Cohort Profile:DOLORisk Dundee: a longitudinal study of chronic neuropathic pain

Purpose Neuropathic pain is a common disorder of the somatosensory system that affects 7%–10% of the general population. The disorder places a large social and economic burden on patients as well as healthcare services. However, not everyone with a relevant underlying aetiology develops corresponding pain. DOLORisk Dundee, a European Union-funded cohort, part of the multicentre DOLORisk consortium, was set up to increase current understanding of this variation in onset. In particular, the cohort will allow exploration of psychosocial, clinical and genetic predictors of neuropathic pain onset.Participants DOLORisk Dundee has been constructed by rephenotyping two pre-existing Scottish population cohorts for neuropathic pain using a standardised ‘core’ study protocol: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) (n=5236) consisting of predominantly type 2 diabetics from the Tayside region, and Generation Scotland: Scottish Family Health Study (GS:SFHS; n=20 221). Rephenotyping was conducted in two phases: a baseline postal survey and a combined postal and online follow-up survey. DOLORisk Dundee consists of 9155 participants (GoDARTS=1915; GS:SFHS=7240) who responded to the baseline survey, of which 6338 (69.2%; GoDARTS=1046; GS:SFHS=5292) also responded to the follow-up survey (18 months later).Findings to date At baseline, the proportion of those with chronic neuropathic pain (Douleur Neuropathique en 4 Questions questionnaire score ≥3, duration ≥3 months) was 30.5% in GoDARTS and 14.2% in Generation Scotland. Electronic record linkage enables large scale genetic association studies to be conducted and risk models have been constructed for neuropathic pain.Future plans The cohort is being maintained by an access committee, through which collaborations are encouraged. Details of how to do this will be available on the study website (http://dolorisk.eu/). Further follow-up surveys of the cohort are planned and funding applications are being prepared to this effect. This will be conducted in harmony with similar pain rephenotyping of UK Biobank

No-Scale Solution to Little Hierarchy

We show that the little hierarchy problem can be solved in the no-scale supergravity framework. In this model the supersymmetry breaking scale is generated when the electroweak symmetry breaking condition is satisfied and therefore, unlike usual supersymmetric models, the correlation between the electroweak symmetry breaking scale and the average stop mass scale can be justified. This correlation solves the little hierarchy puzzle. Using minimal supergravity boundary conditions, we find that the parameter space predicted by no-scale supergravity is allowed by all possible experimental constraints. The predicted values of supersymmetric particle masses are low enough to be very easily accessible at the LHC. This parameter space will also be probed in the upcoming results from the dark matter direct detection experiments.Comment: 15 pages, 2 figure

Natural Predictions for the Higgs Boson Mass and Supersymmetric Contributions to Rare Processes

In the context of No-Scale F-SU(5), a model defined by the convergence of the F-lipped SU(5) Grand Unified Theory, two pairs of hypothetical TeV scale vector-like supersymmetric multiplets with origins in F-theory, and the dynamically established boundary conditions of No-Scale Supergravity, we predict that the lightest CP-even Higgs boson mass lies within the range of 119.0 GeV to 123.5 GeV, exclusive of the vector-like particle contribution to the mass. With reports by the CMS, ATLAS, CDF, and D0 Collaborations detailing enticing statistical excesses in the vicinity of 120 GeV in searches for the Standard Model Higgs boson, all signs point to an imminent discovery. While basic supersymmetric constructions such as mSUGRA and the CMSSM have already suffered overwhelming reductions in viable parameterization during the LHC's initial year of operation, about 80% of the original No-Scale F-SU(5) model space remains viable after analysis of the first 1.1 fb^{-1} of integrated luminosity. This model is moreover capable of handily explaining the small excesses recently reported in the CMS multijet supersymmetry search, and also features a highly favorable "golden" subspace which may simultaneously account for the key rare process limits on the muon anomalous magnetic moment (g - 2) and the branching ratio of the flavor-changing neutral current decay b to s\gamma. In addition, the isolated mass parameter responsible for the global particle mass normalization, the gaugino boundary mass M_{1/2}, is dynamically determined at a secondary local minimization of the minimum of the Higgs potential V_{min}, in a manner which is deeply consistent with all precision measurements at the physical electroweak scale.Comment: Physics Letters B Version, 10 pages, 2 figures, 2 table