Bias-Variation Dilemma Challenges Clinical Trials: Inherent Limitations of Randomized Controlled Trials and Meta-Analyses Comparing Hernia Therapies

Purpose: Evaluation of hernia therapies according to the current rules of Evidence Based Medicine is widely reduced to results of RCTs or meta-analyses. RCTs have been accepted as a most important tool to confirm a superior effect of an intervention. Unfortunately, in hernia surgery, comparisons of RCTs and correspondingly their use in meta-analyses, are not, surprisingly often, able to confirm any significant impact of a specific procedure due to intrinsic restrictions in a multi-causal\ud setting with its web of influences. Methods: Based on our own experiences of clinical studies in surgery, the present article outlines several situations, with their respective reasons, which argue the severe limitations of RCTs and meta-analysis to define an optimum treatment. Results: Metaanalyses accumulate the variations of each trial, which then may cover any clear causal relationship. RCTs usually are dealing with subgroups of standard patients thus excluding the majority of our patients. Low statistical power of current cohort sizes restricts the analysis of subgroups or of effects with low incidences. Simple comparisons of means frequently are hampered by nonlinear relationships to outcome. The relevance of a specific variable is difficult to separate from other influences. The limited surveillance period of studies ignores a delayed change in outcome. Randomization cannot guarantee a standardized patient’s condition. All the arguments have to be considered as a crucial and fundamental consequence of the bias-variance dilemma or principle of uncertainty in medicine, and underline the many limitations of RCTs to evaluate any specific impact of hernia therapies on e.g. infection, pain or recurrence. Conclusions: Many surgical issues\ud cannot be and should not be investigated by RCTs, in particular, if a marked patients’ heterogeneity\ud has to be considered or the low incidences of the outcome readout cannot be addressed with sufficient statistical power without getting lost in the variation mire. Registries with their non-restricted data-acquisition should be regarded as reliable alternatives for postoperative outcome quality surveillance studies

Beam test evaluation of electromagnetic calorimeter modules made from proton-damaged PbWO_4 crystals

The performance of electromagnetic calorimeter modules made of proton-irradiated PbWO_4 crystals has been studied in beam tests. The modules, similar to those used in the Endcaps of the CMS electromagnetic calorimeter (ECAL), were formed from 5×5 matrices of PbWO_4 crystals, which had previously been exposed to 24 GeV protons up to integrated fluences between 2.1× 10^(13) and 1.3× 10^(14) cm^(−2). These correspond to the predicted charged-hadron fluences in the ECAL Endcaps at pseudorapidity η = 2.6 after about 500 fb^(−1) and 3000 fb^(−1) respectively, corresponding to the end of the LHC and High Luminosity LHC operation periods. The irradiated crystals have a lower light transmission for wavelengths corresponding to the scintillation light, and a correspondingly reduced light output. A comparison with four crystals irradiated in situ in CMS showed no significant rate dependence of hadron-induced damage. A degradation of the energy resolution and a non-linear response to electron showers are observed in damaged crystals. Direct measurements of the light output from the crystals show the amplitude decreasing and pulse becoming faster as the fluence increases. The latter is interpreted, through comparison with simulation, as a side-effect of the degradation in light transmission. The experimental results obtained can be used to estimate the long term performance of the CMS ECAL

Evaluation of a urine pooling strategy for the rapid and cost-efficient prevalence classification of schistosomiasis

A key epidemiologic feature of schistosomiasis is its focal distribution, which has important implications for the spatial targeting of preventive chemotherapy programs. We evaluated the diagnostic accuracy of a urine pooling strategy using a point-of-care circulating cathodic antigen (POC-CCA) cassette test for detection of Schistosoma mansoni, and employed simulation modeling to test the classification accuracy and efficiency of this strategy in determining where preventive chemotherapy is needed in low-endemicity settings.; We performed a cross-sectional study involving 114 children aged 6-15 years in six neighborhoods in Azaguié Ahoua, south Côte d'Ivoire to characterize the sensitivity and specificity of the POC-CCA cassette test with urine samples that were tested individually and in pools of 4, 8, and 12. We used a Bayesian latent class model to estimate test characteristics for individual POC-CCA and quadruplicate Kato-Katz thick smears on stool samples. We then developed a microsimulation model and used lot quality assurance sampling to test the performance, number of tests, and total cost per school for each pooled testing strategy to predict the binary need for school-based preventive chemotherapy using a 10% prevalence threshold for treatment.; The sensitivity of the urine pooling strategy for S. mansoni diagnosis using pool sizes of 4, 8, and 12 was 85.9%, 79.5%, and 65.4%, respectively, when POC-CCA trace results were considered positive, and 61.5%, 47.4%, and 30.8% when POC-CCA trace results were considered negative. The modeled specificity ranged from 94.0-97.7% for the urine pooling strategies (when POC-CCA trace results were considered negative). The urine pooling strategy, regardless of the pool size, gave comparable and often superior classification performance to stool microscopy for the same number of tests. The urine pooling strategy with a pool size of 4 reduced the number of tests and total cost compared to classical stool microscopy.; This study introduces a method for rapid and efficient S. mansoni prevalence estimation through examining pooled urine samples with POC-CCA as an alternative to widely used stool microscopy

Search for dark matter produced in association with heavy-flavor quark pairs in proton-proton collisions at √s = 13 TeV

A search is presented for an excess of events with heavy-flavor quark pairs (tt and bb) and a large imbalance in transverse momentum in data from proton–proton collisions at a center-of-mass energy of 13 TeV. The data correspond to an integrated luminosity of 2.2fb^(−1) collected with the CMS detector at the CERN LHC. No deviations are observed with respect to standard model predictions. The results are used in the first interpretation of dark matter production in tt and bb final states in a simplified model. This analysis is also the first to perform a statistical combination of searches for dark matter produced with different heavy-flavor final states. The combination provides exclusions that are stronger than those achieved with individual heavy-flavor final states

Measurement of the B^± Meson Nuclear Modification Factor in Pb-Pb Collisions at √S_(NN) = 5.02 TeV

The differential production cross sections of B^± mesons are measured via the exclusive decay channels B^± → J/ψK^ ±→ μ^+μ^−K^± as a function of transverse momentum in pp and Pb-Pb collisions at a center-of-mass energy √S_(NN) = 5.02  TeV per nucleon pair with the CMS detector at the LHC. The pp(Pb-Pb) data set used for this analysis corresponds to an integrated luminosity of 28.0  pb^(-1) (351  μb^(-1)). The measurement is performed in the B^± meson transverse momentum range of 7 to 50  GeV/c, in the rapidity interval |y| < 2.4. In this kinematic range, a strong suppression of the production cross section by about a factor of 2 is observed in the Pb-Pb system in comparison to the expectation from pp reference data. These results are found to be roughly compatible with theoretical calculations incorporating beauty quark diffusion and energy loss in a quark-gluon plasma

Constraints on the double-parton scattering cross section from same-sign W boson pair production in proton-proton collisions at √s = 8 TeV

A first search for same-sign WW production via double-parton scattering is performed based on proton-proton collision data at a center-of-mass energy of 8 TeV using dimuon and electron-muon final states. The search is based on the analysis of data corresponding to an integrated luminosity of 19.7 fb^(−1). No significant excess of events is observed above the expected single-parton scattering yields. A 95% confidence level upper limit of 0.32 pb is set on the inclusive cross section for same-sign WW production via the double-parton scattering process. This upper limit is used to place a 95% confidence level lower limit of 12.2 mb on the effective double-parton cross section parameter, closely related to the transverse distribution of partons in the proton. This limit on the effective cross section is consistent with previous measurements as well as with Monte Carlo event generator predictions

Search for t t-bar resonances in highly boosted lepton+jets and fully hadronic final states in proton-proton collisions at √s = 13 TeV

A search for the production of heavy resonances decaying into top quark-antiquark pairs is presented. The analysis is performed in the lepton+jets and fully hadronic channels using data collected in proton-proton collisions at √s = 13 TeV using the CMS detector at the LHC, corresponding to an integrated luminosity of 2.6 fb^(−1). The selection is optimized for massive resonances, where the top quarks have large Lorentz boosts. No evidence for resonant t t-bar production is found in the data, and upper limits on the production cross section of heavy resonances are set. The exclusion limits for resonances with masses above 2 TeV are significantly improved compared to those of previous analyses at √s = 8 TeV

Search for top quark partners with charge 5/3 in proton-proton collisions at √s = 13 TeV

A search for the production of heavy partners of the top quark with charge 5/3 (X_(5/3)) decaying into a top quark and a W boson is performed with a data sample corresponding to an integrated luminosity of 2.3 fb^(−1), collected in proton-proton collisions at a center-of-mass energy of 13 TeV with the CMS detector at the CERN LHC. Final states with either a pair of same-sign leptons or a single lepton, along with jets, are considered. No significant excess is observed in the data above the expected standard model background contribution and an X_(5/3) quark with right-handed (left-handed) couplings is excluded at 95% confidence level for masses below 1020 (990) GeV. These are the first limits based on a combination of the same-sign dilepton and the single-lepton final states, as well as the most stringent limits on the X_(5/3) mass to date

Measurements of ttcross sections in association with b jets and inclusive jets and their ratio using dilepton final states in pp collisions at √s = 13 TeV

The cross sections for the production of ttbb and ttjj events and their ratio σ_(ttbb)/_(ttjj) are measured using data corresponding to an integrated luminosity of 2.3 fb^(−1) collected in pp collisions at √s = 13 TeV with the CMS detector at the LHC. Events with two leptons (e or μ) and at least four reconstructed jets, including at least two identified as b quark jets, in the final state are selected. In the full phase space, the measured ratio is 0.022 ± 0.003(stat) ± 0.006(syst), the cross section σ_(ttbb) is 4.0 ± 0.6(stat) ± 1.3(syst)pb and σ_(ttjj) is 184 ± 6(stat) ± 33(syst)pb. The measurements are compared with the standard model expectations obtained from a powheg simulation at next-to-leading-order interfaced with pythia

Combination of searches for heavy resonances decaying to WW, WZ, ZZ, WH, and ZH boson pairs in proton–proton collisions at √s = 8 and 13 TeV

A statistical combination of searches is presented for massive resonances decaying to WW, WZ, ZZ, WH, and ZH boson pairs in proton–proton collision data collected by the CMS experiment at the LHC. The data were taken at centre-of-mass energies of 8 and 13 TeV, corresponding to respective integrated luminosities of 19.7 and up to 2.7 fb^(−1). The results are interpreted in the context of heavy vector triplet and singlet models that mimic properties of composite-Higgs models predicting W′ and Z′ bosons decaying to WZ, WW, WH, and ZH bosons. A model with a bulk graviton that decays into WW and ZZ is also considered. This is the first combined search for WW, WZ, WH, and ZH resonances and yields lower limits on masses at 95% confidence level for W′ and Z′ singlets at 2.3 TeV, and for a triplet at 2.4 TeV. The limits on the production cross section of a narrow bulk graviton resonance with the curvature scale of the warped extra dimension k = 0.5, in the mass range of 0.6 to 4.0 TeV, are the most stringent published to date