Hub and spoke framework for study of surgical centralization within United States health systems.

BACKGROUND: Hospital consolidation into health systems has mixed effects on surgical quality, potentially related to degree of surgical centralization at high-volume (hub) sites. We developed a novel measure of centralization and evaluated a hub and spoke framework. METHODS: Surgical centralization within health systems was measured using hospital surgical volumes (American Hospital Association) and health system data (Agency for Healthcare Research and Quality). Hub and spoke hospitals were compared using mixed effects logistic regression and system characteristics associated with surgical centralization were identified using a linear model. RESULTS: Within 382 health systems containing 3022 hospitals, system hubs perform 63% of cases (IQR 40-84%). Hubs are larger, in metropolitan and urban areas, and more often academically affiliated. Degree of surgical centralization varies ten-fold. Larger, multistate, and investor-owned systems are less centralized. Adjusting for these factors, there is less centralization among teaching systems (p â€‹< â€‹0.001). CONCLUSIONS: A hub-spoke framework applies to most health systems but centralization varies significantly. Future studies of health system surgical care should assess the contributions of surgical centralization and teaching status on differential quality.

Patients undergoing colorectal surgery at a Veterans Affairs Hospital do not experience racial disparity in length of stay either before or after implementing an enhanced recovery pathway.

BACKGROUND: Enhanced Recovery Pathways (ERP) have been shown to reduce racial disparities following surgery. The objective of this study is to determine whether ERP implementation mitigates racial disparities at a Veterans Affairs Hospital. METHODS: A retrospective cohort study was conducted using data obtained from the Veterans Affairs Surgical Quality Improvement Program. All patients undergoing elective colorectal surgery following ERP implementation were included. Current procedural terminology (CPT) codes were used to identify patients who underwent similar procedures prior to ERP implementation. RESULTS: Our study included 417 patients (314 pre-ERP vs. 103 ERP), 97.1% of which were male, with an average age of 62.32 (interquartile range (IQR): 25-90). ERP patients overall had a significantly shorter post-operative length of stay (pLOS) vs. pre-ERP patients (median 4 days (IQR: 3-6.5) vs. 6 days (IQR: 4-9) days (p < 0.001)). Within the pre-ERP group, median pLOS for both races was 6 days (IQR: 4-6; p < 0.976) and both groups experienced a decrease in median pLOS (4 vs. 6 days; p < 0.009 and p < 0.001) following ERP implementation. CONCLUSIONS: Racial disparities did not exist in patients undergoing elective surgery at a single VA Medical Center. Implementation of an ERP significantly reduced pLOS for black and white patients.

Methyltransferase G9A Regulates Osteogenesis via Twist Gene Repression.

Here we investigate the role of epigenetic factors in controlling the timing of cranial neural crest cell differentiation. The gene coding for histone H3 lysine 9 methyltransferase G9A was conditionally deleted in neural crest cells with Wnt1-Cre. The majority of homozygous-null animals survived to birth but thereafter failed to thrive. Phenotypic analysis of postnatal animals revealed that the mutants displayed incomplete ossification and 20% shorter jaws as compared to their wild-type littermates. At E13.5, patterns of expression of the osteogenic transcription factor RUNX2 and the mesenchymal transcription factor TWIST are similar in controls and mutants; both overlap in areas of future intramembranous bone formation. At E14.5, the nonosteogenic mesenchyme expressed TWIST, whereas the ossification center had strong RUNX2 and osteopontin expression. In the mutants, TWIST protein was present in the osteogenic mesenchyme, while osteopontin was not expressed until E15.5. In addition, in mutants, small regions of TWIST-positive osteogenic mesenchyme were visible until E15.5. The delay in ossification and reduction in size of the ossification centers were correlated with an earlier decrease in proliferation. We used micromass cultures of the face to investigate the direct effects of G9A inhibition on skeletal differentiation. Addition of a small molecule inhibitor for G9A, BIX-01294, to wild-type cells upregulated Twist genes similar to what was observed in vivo. The inhibitor also caused decreases in several osteogenic markers. Chromatin immunoprecipitation analysis of primary osteogenic mesenchyme from calvaria revealed that Twist1 and Twist2 regulatory regions contain the repressive H3K9me2 marks catalyzed by G9A, which are removed when BIX-01294 is added. Our results establish a role for G9A and H3K9me2 in the regulation of Twist genes and provide novel insights into the significance of epigenetic mechanisms in controlling temporal and tissue-specific gene expression during development.

Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome.

The study of rare genetic diseases provides valuable insights into human gene function. Here, we investigate dominant Robinow syndrome (RS), which affects the WNT5A signaling pathway. Autosomal dominant RS is caused by missense mutations in WNT5A or nonsense mutations in the adaptor protein DVL1 or DVL3. The recessive form of the disease is caused by loss-of-function mutations in the receptor ROR2. RS is characterized by hypertelorism, midface, and mandibular hypoplasia. Here, we focus on the missense mutations in WNT5A, since the impact on function is difficult to predict from in silico analysis. We used chicken embryo to express wild-type or 2 mutant versions of human WNT5A in the mandible and then examined the morphologic, cellular, and molecular effects. The 3 experimental viruses-wt WNT5A, WNT5AC83S, or WNT5AC182R-all caused shortening of the mandible on the injected side as compared with GFP controls. Although the phenotypes initially appeared similar, we uncovered specific disruption of chondrocyte polarity and shape, inhibition of cell migration, differences in target gene expression, and absence of JNK signaling only in the presence of mutant viruses. In addition, the missense mutations do not appear to block receptor binding, since in paracrine experiments, the mutant protein inhibits cell migration. In this study, we ruled out a straightforward gain or loss of function caused by the WNT5A missense mutations. Instead, the mutations are likely redirecting WNT signaling away from JNK-PCP toward other noncanonical pathways. We conclude that in RS, WNT5A missense mutations have dominant neomorphic effects that interfere with the function of the wild-type protein.

SPARCS and Pelli-Robson contrast sensitivity testing in normal controls and patients with cataract.

PurposeTo determine the ability of the newly developed internet-based Spaeth/Richman Contrast Sensitivity (SPARCS) test to assess contrast sensitivity centrally and peripherally in cataract subjects and controls, in comparison with the Pelli-Robson (PR) test.MethodsIn this prospective cross-sectional study, cataract subjects and age-matched normal controls were evaluated using the SPARCS and PR tests. Contrast sensitivity testing was performed in each eye twice in a standardized testing environment in randomized order. SPARCS scores were obtained for central, right upper (RUQ), right lower (RLQ), left upper (LUQ), and left lower quadrants (LLQ). PR scores were obtained for central contrast sensitivity. PR and SPARCS scores in cataract subjects were compared with controls. Intraclass correlation coefficients (ICC) and Bland Altman analysis were used to determine test-retest reliability and correlation.ResultsA total of 162 eyes from 84 subjects were analyzed: 43 eyes from 23 cataract subjects, and 119 eyes from 61 controls. The mean scores for SPARCS centrally were 13.4 and 14.5 in the cataract and control groups, respectively (P=0.001). PR mean scores were 1.31 and 1.45 in cataract and control groups, respectively (P<0.001). ICC values for test-retest reliability for cataract subjects were 0.75 for PR and 0.61 for the SPARCS total. There was acceptable agreement between the ability of PR and SPARCS to detect the effect of cataract on central contrast sensitivity.ConclusionsBoth SPARCS and PR demonstrate a significant influence of cataract on contrast sensitivity. SPARCS offers the advantage of determining contrast sensitivity peripherally and centrally, without being influenced by literacy.

Observation of B→D(*) π

We report on measurements of the decays of B¯ mesons into the semileptonic final states B¯â†’D^(*)π^(+)π^(-)ℓ^(-)ν¯, where D^(*) represents a D or D^(*) meson and ℓ^(-) is an electron or a muon. These measurements are based on 471×10^(6) BB ¯ pairs recorded with the BABAR detector at the SLAC asymmetric B factory PEP-II. We determine the branching fraction ratios R_{π^{+}π^{-}}^{(*)}=B(B[over ¯]→D^{(*)}π^{+}π^{-}ℓ^{-}ν[over ¯])/B(B[over ¯]→D^{(*)}ℓ^{-}ν[over ¯]) using events in which the second B meson is fully reconstructed. We find R_{π^{+}π^{-}}=0.067±0.010±0.008 and R_{π^{+}π^{-}}^{*}=0.019±0.005±0.004, where the first uncertainty is statistical and the second is systematic. Based on these results and assuming isospin invariance, we estimate that B[over ¯]→D^{(*)}ππℓ^{-}ν[over ¯] decays, where π denotes either a π^{±} and π^{0} meson, account for up to half the difference between the measured inclusive semileptonic branching fraction to charm hadrons and the corresponding sum of previously measured exclusive branching fractions.

Search for Long-Lived Particles in e+ e- Collisions.

We present a search for a neutral, long-lived particle L that is produced in e+ e- collisions and decays at a significant distance from the e+ e- interaction point into various flavor combinations of two oppositely charged tracks. The analysis uses an e+ e- data sample with a luminosity of 489.1 fb(-1) collected by the BABAR detector at the ϒ(4S), ϒ(3S), and ϒ(2S) resonances and just below the ϒ(4S). Fitting the two-track mass distribution in search of a signal peak, we do not observe a significant signal, and set 90% confidence level upper limits on the product of the L production cross section, branching fraction, and reconstruction efficiency for six possible two-body L decay modes as a function of the L mass. The efficiency is given for each final state as a function of the mass, lifetime, and transverse momentum of the candidate, allowing application of the upper limits to any production model. In addition, upper limits are provided on the branching fraction B(B→XsL), where Xs is a strange hadronic system.

Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors.

BACKGROUND: The use of Escherichia coli purine nucleoside phosphorylase (PNP) to activate fludarabine has demonstrated safety and antitumor activity during preclinical analysis and has been approved for clinical investigation. PATIENTS AND METHODS: A first-in-human phase I clinical trial (NCT 01310179; IND 14271) was initiated to evaluate safety and efficacy of an intratumoral injection of adenoviral vector expressing E. coli PNP in combination with intravenous fludarabine for the treatment of solid tumors. The study was designed with escalating doses of fludarabine in the first three cohorts (15, 45, and 75 mg/m(2)) and escalating virus in the fourth (10(11)-10(12) viral particles, VP). RESULTS: All 12 study subjects completed therapy without dose-limiting toxicity. Tumor size change from baseline to final measurement demonstrated a dose-dependent response, with 5 of 6 patients in cohorts 3 and 4 achieving significant tumor regression compared with 0 responsive subjects in cohorts 1 and 2. The overall adverse event rate was not dose-dependent. Most common adverse events included pain at the viral injection site (92%), drainage/itching/burning (50%), fatigue (50%), and fever/chills/influenza-like symptoms (42%). Analysis of serum confirmed the lack of systemic exposure to fluoroadenine. Antibody response to adenovirus was detected in two patients, suggesting that neutralizing immune response is not a barrier to efficacy. CONCLUSIONS: This first-in-human clinical trial found that localized generation of fluoroadenine within tumor tissues using E. coli PNP and fludarabine is safe and effective. The pronounced effect on tumor volume after a single treatment cycle suggests that phase II studies are warranted. CLINICALTRIALSGOV IDENTIFIER: NCT01310179.

Study of CP asymmetry in B

We present a measurement of the asymmetry A_{CP} between same-sign inclusive dilepton samples ℓ^{+}ℓ^{+} and ℓ^{-}ℓ^{-} (ℓ=e, µ) from semileptonic B decays in ϒ(4S)→BB[over ¯] events, using the complete data set recorded by the BABAR experiment near the ϒ(4S) resonance, corresponding to 471×10^{6} BB[over ¯] pairs. The asymmetry A_{CP} allows comparison between the mixing probabilities P(B[over ¯]^{0}→B^{0}) and P(B^{0}→B[over ¯]^{0}), and therefore probes CP and T violation. The result, A_{CP}=[-3.9±3.5(stat)±1.9(syst)]×10^{-3}, is consistent with the standard model expectation.

Search for a dark photon in e(+)e(-) collisions at BABAR.

Dark sectors charged under a new Abelian interaction have recently received much attention in the context of dark matter models. These models introduce a light new mediator, the so-called dark photon (A^{'}), connecting the dark sector to the standard model. We present a search for a dark photon in the reaction e^{+}e^{-}→γA^{'}, A^{'}→e^{+}e^{-}, µ^{+}µ^{-} using 514 fb^{-1} of data collected with the BABAR detector. We observe no statistically significant deviations from the standard model predictions, and we set 90% confidence level upper limits on the mixing strength between the photon and dark photon at the level of 10^{-4}-10^{-3} for dark photon masses in the range 0.02-10.2 GeV. We further constrain the range of the parameter space favored by interpretations of the discrepancy between the calculated and measured anomalous magnetic moment of the muon.

Measurement of the D*(2010)+ meson width and the D*(2010)+ - D0 mass difference.

We measure the mass difference Δm0 between the D*(2010)+ and the D0 and the natural linewidth Γ of the transition D*(2010)+ → D0π+. The data were recorded with the BABAR detector at center-of-mass energies at and near the Υ(4S) resonance, and correspond to an integrated luminosity of approximately 477 fb(-1). The D0 is reconstructed in the decay modes D0 → K- π+ and D0 → K- π+ π- π+. For the decay mode D0 → K- π+ we obtain Γ = (83.4±1.7±1.5) keV and Δm0 = (145425.6±0.6±1.7) keV, [corrected] where the quoted errors are statistical and systematic, respectively. For the D0 → K- π+ π- π+ mode we obtain Γ = (83.2±1.5±2.6) keV and Δm0 = (145426.6±0.5±1.9) keV. [corrected] The combined measurements yield Γ = (83.3±1.2±1.4) keV and Δm0 = (145425.9±0.4±1.7) keV; the width is a factor of approximately 12 times more precise than the previous value, while the mass difference is a factor of approximately 6 times more precise.

Expression, function and regulation of Evi-1 during embryonic avian development.

Ecotropical viral integration site 1 (Evi-1) is a transcription factor essential for vascularisation and cell proliferation during embryonic development. The chimeric transcription factor AML1-EVI-1 is activated in leukaemia where it plays a role as a differentiation block and stimulator of proliferation. Here, we cloned chicken Evi-1 and analysed its expression during embryonic development. There was early expression in the pharyngeal arches, in the brain and intermediate mesoderm of chicken embryos at stage 15. Later at stage 20, Evi-1 mesenchymal expression was concentrated in the second pharyngeal arch, and weaker expression was found in the mandibular and maxillary prominences. Facial expression decreased in intensity during development. Evi-1 expression in the limb was also limited to the mesenchyme with the most prominent expression in the anterior margin. Evi-1 was not detectable in the posterior limb bud. At later stages, Evi-1 was expressed in the peripheral mesenchyme of the limb but not in the developing precartilage blastema. At stage 29, the expression became restricted to the perichondrium and interdigital areas; however, the cartilage condensations themselves were negative. To study the function of Evi-1 in chondrogenesis, we knocked down expression in limb micromass cultures using siRNA. Chondrogenesis was significantly reduced in both anterior and posterior cultures. Since Evi-1 was expressed adjacent to the apical ectodermal ridge and this area is a source of FGFs, we tested whether endogenous FGF receptor signalling was necessary to maintain its expression. Inhibitors of FGFRs (PD161570 and SU5402) were applied to wing mesenchyme, and downregulation of Evi-1 expression was observed after treatment with both inhibitors. Therefore, Evi-1 may be a transcription factor mediating the effects of FGF and may also be defining the size of cartilage elements in the limb.

ONJ in two dental practice-based research network regions.

The incidence of osteonecrosis of the jaw (ONJ) in the population is low, but specifics are unknown. Potential risk factors include bisphosphonate treatment, steroid treatment, osteoporosis, and head/neck radiation. This Dental Practice-Based Research Network study estimated ONJ incidence and odds ratios from bisphosphonate exposure and other risk factors using a key word search and manual chart reviews of electronic records for adults aged > or = 35 years enrolled during 1995-2006 in 2 large health care organizations. We found 16 ONJ cases among 572,606 cohort members; 7 additional cases were identified through dental plan resources. Among 23 cases (0.63 per 100,000 patient years), 20 (87%) had at least 1 risk factor, and 6 (26%) had received oral bisphosphonates. Patients with oral bisphosphonates were 15.5 (CI, 6.0-38.7) more likely to have ONJ than non-exposed patients; however, the sparse number of ONJ cases limits firm conclusions and suggests that the absolute risks for ONJ from oral bisphosphonates is low.

Search for CP violation in B0-B0 mixing using partial reconstruction of B0→D*- Xℓ+ νℓ and a kaon tag.

We present results of a search for CP violation in B0- B0 mixing with the BABAR detector. We select a sample of B0→D*- Xℓ+ ν decays with a partial reconstruction method and use kaon tagging to assess the flavor of the other B meson in the event. We determine the CP violating asymmetry ACP≡[N(B0B0)-N(B0B0)]/[N(B0B0)+N(B0B0)]=(0.06±0.17(-0.32)(+0.38))%, corresponding to ΔCP=1-|q/p|=(0.29±0.84(-1.61)(+1.88))×10(-3).

Precision measurement of the B → Xs γ photon energy spectrum, branching fraction, and direct CP asymmetry A(CP)((B → X(s+d)γ).

The photon spectrum in the inclusive electromagnetic radiative decays of the B meson, B → X(s)γ plus B → X(d)γ, is studied using a data sample of (382.8 ± 4.2) × 10(6)Υ(4S) → BB decays collected by the BABAR experiment at SLAC. The spectrum is used to extract the branching fraction B(B → X(s)γ) = (3.21 ± 0.33) × 10(-4) for E(γ) >1.8 GeV and the direct CP asymmetry A(CP) (B → X(s+d)γ) = 0.057 ± 0.063. The effects of detector resolution and Doppler smearing are unfolded to measure the photon energy spectrum in the B meson rest frame.

Observation of time-reversal violation in the B0 meson system.

Although CP violation in the B meson system has been well established by the B factories, there has been no direct observation of time-reversal violation. The decays of entangled neutral B mesons into definite flavor states (B(0) or B(0)), and J/ψK(L)(0) or ccK(S)(0) final states (referred to as B(+) or B(-)), allow comparisons between the probabilities of four pairs of T-conjugated transitions, for example, B(0) → B(-) and B(-) → B(0), as a function of the time difference between the two B decays. Using 468 × 10(6) BB pairs produced in Υ(4S) decays collected by the BABAR detector at SLAC, we measure T-violating parameters in the time evolution of neutral B mesons, yielding ΔS(T)(+) = -1.37 ± 0.14(stat) ± 0.06(syst) and ΔS(T)(-) = 1.17 ± 0.18(stat) ± 0.11(syst). These nonzero results represent the first direct observation of T violation through the exchange of initial and final states in transitions that can only be connected by a T-symmetry transformation.

Evidence for an excess of B→D*τ(-)ν(τ) decays.

Based on the full BABAR data sample, we report improved measurements of the ratios R(D(*))=B(B[over ¯]→D(*)τ(-)ν[over ¯](τ))/B(B[over ¯]→D(*)ℓ(ℓ)(-)ν[over ¯](ℓ)), where ℓ is either e or µ. These ratios are sensitive to new physics contributions in the form of a charged Higgs boson. We measure R(D)=0.440±0.058±0.042 and R(D(*))=0.332±0.024±0.018, which exceed the standard model expectations by 2.0σ and 2.7σ, respectively. Taken together, our results disagree with these expectations at the 3.4σ level. This excess cannot be explained by a charged Higgs boson in the type II two-Higgs-doublet model.

Search for low-mass dark-sector Higgs bosons.

Recent astrophysical and terrestrial experiments have motivated the proposal of a dark sector with GeV-scale gauge boson force carriers and new Higgs bosons. We present a search for a dark Higgs boson using 516 fb(-1) of data collected with the BABAR detector. We do not observe a significant signal and we set 90% confidence level upper limits on the product of the standard model-dark-sector mixing angle and the dark-sector coupling constant.