Classical and quantum many-body effects on the critical properties and thermodynamic regularities of silicon.

Using molecular simulation, we determine the critical properties of Si as well as the loci for several remarkable thermodynamic contours spanning the supercritical region of the phase diagram. We consider a classical three-body potential as well as a quantum (tight-binding) many-body model, and determine the loci for the ideality contours, including the Zeno line and the H line of ideal enthalpy. The two strategies (classical or quantum) lead to strongly asymmetric binodals and to critical properties in good agreement with each other. The Zeno and H lines are found to remain linear over a wide temperature interval, despite the changes in electronic structure undergone by the fluid along these contours. We also show that the classical and quantum model yield markedly different results for the parameters defining the H line, the exponents for the power-laws underlying the line of minima for the isothermal enthalpy and for the density required to achieve ideal behavior, most notably for the enthalpy.

The impact of tabalumab on the kidney in systemic lupus erythematosus: results from two phase 3 randomized, clinical trials.

INTRODUCTION: Tabalumab is a monoclonal antibody that neutralizes membrane and soluble B-cell activating factor. Two 52-week, randomized, double-blind, placebo controlled phase 3 trials evaluated the safety and efficacy of tabalumab in systemic lupus erythematosus. METHODS: Patients with moderate to severe active systemic lupus erythematosus (without severe active lupus nephritis) were randomly assigned 1:1:1 to receive tabalumab (120 mg subcutaneously every 2 or 4 weeks) or placebo for 52 weeks. Serum creatinine concentration, estimated glomerular filtration rate, urine protein/creatinine ratio, renal flares and renal adverse events were determined monthly. Data were analyzed for the intent-to-treat population and for intent-to-treat patients with baseline urine protein/creatinine ratio >20 mg/mmol (intent-to-treat plus urine protein/creatinine ratio). RESULTS: The trials enrolled 2262 patients. At baseline, demographics, systemic lupus erythematosus disease activity, serum creatinine concentration, estimated glomerular filtration rate and urine protein/creatinine ratio were similar among the treatment arms (with the exception of disease duration). In the intent-to-treat and intent-to-treat plus urine protein/creatinine ratio populations, there were no differences between the arms in the baseline-to-endpoint change in serum creatinine concentration, glomerular filtration rate, urine protein/creatinine ratio, or renal flare rates. Tabalumab resulted in a significant B-cell reduction and decreased immunoglobulin G levels at both doses. CONCLUSIONS: Compared to placebo, tabalumab did not significantly affect the serum creatinine concentration, glomerular filtration rate, urine protein/creatinine ratio, or renal flare rates over 1 year in intent-to-treat or intent-to-treat plus urine protein/creatinine ratio patients. There were no significant renal safety signals.ClinicalTrials.gov identifiers: NCT01205438 and NCT01196091 Lupus (2016) 25, 1597-1601.

Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study.

OBJECTIVES: To evaluate the efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that neutralises membrane and soluble B-cell activating factor (BAFF). METHODS: This randomised, placebo-controlled study enrolled 1124 patients with moderate-to-severe systemic lupus erythematosus (SLE) (Safety of Estrogens in Lupus Erythematosus National Assessment- SLE Disease Activity Index ≥6 at baseline). Patients received standard of care plus subcutaneous study drug, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every 2 weeks (120 Q2W), 120 mg every 4 weeks (120 Q4W) or placebo. Primary endpoint was proportion achieving SLE Responder Index 5 (SRI-5) improvement at week 52. RESULTS: Clinical characteristics were balanced across groups. The primary endpoint was met with 120 Q2W (38.4% vs 27.7%, placebo; p=0.002), but not with the less frequent 120 Q4W regimen (34.8%, p=0.051). Although key secondary endpoints (time to severe flare, corticosteroid sparing and fatigue) were not met, patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician's Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins. The incidences of deaths, serious adverse events (AEs), and treatment-emergent AEs were similar in the 120 Q2W, 120 Q4W and placebo groups, but depression and suicidal ideation, albeit rare events, were more commonly reported with tabalumab. CONCLUSION: SRI-5 was met with 120 Q2W and although key secondary endpoints were not met, numerous other secondary endpoints significantly improved in addition to pharmacodynamic evidence of BAFF pathway blockade. The safety profile for tabalumab was similar to placebo, except for depression and suicidality, which were uncommon. TRIAL REGISTRATION NUMBER: NCT01205438.

Prophylactic use of anti-emetic medications reduced nausea and vomiting associated with exenatide treatment: a retrospective analysis of an open-label, parallel-group, single-dose study in healthy subjects.

AIMS: Transient nausea and, to a lesser extent, vomiting are common adverse effects of exenatide that can be mitigated by dose titration and usually do not result in treatment discontinuation. This retrospective analysis of data from a phase 1, open-label, parallel-group, single-dose study in healthy subjects evaluated the effect of oral anti-emetics on exenatide-associated nausea and vomiting and on the pharmacokinetics of exenatide. METHODS: A single subcutaneous dose (10 µg) of exenatide was administered to 120 healthy subjects (19-65 years, BMI 23-35 kg/m(2) ). Incidences of nausea and vomiting were compared between 60 subjects premedicated with two oral anti-emetics 30 min before the exenatide dose and 60 non-premedicated subjects. Similarly, the area under the concentration-time curve (AUC) and the maximum observed concentration (C(max) ) of plasma exenatide concentrations over 8 h post-dose were compared. RESULTS: Among all subjects [61% male, 32 ± 12 years, body mass index (BMI) 29.1 ± 3.4 kg/m(2) (mean ± sd)], mild to moderate nausea was the most frequent adverse event after exenatide dosing. Vomiting was also observed. Subjects premedicated with anti-emetics experienced significantly less nausea and vomiting (16.7 and 6.7%, respectively) vs. non-premedicated subjects (61.7 and 38.3%, respectively; P-value <0.0001 for both nausea and vomiting). The mean area under the concentration-time curve and the maximum observed concentration AUC and C(max) of plasma exenatide concentrations during 8 h post-dose were not significantly different between groups. CONCLUSION: Administration of oral anti-emetics before a single 10-µg exenatide dose was associated with significant reductions in treatment-emergent nausea and vomiting, with no discernible effect on the pharmacokinetics of exenatide. Use of anti-emetic therapy may provide a short-term strategy to minimize the nausea and vomiting associated with exenatide treatment.

Beyond the Fermi liquid paradigm: hidden Fermi liquids.

An intense investigation of possible non-Fermi liquid states of matter has been inspired by two of the most intriguing phenomena discovered in the past quarter century, namely, high-temperature superconductivity and the fractional quantum Hall effect. Despite enormous conceptual strides, these two fields have developed largely along separate paths. Two widely employed theories are the resonating valence bond theory for high-temperature superconductivity and the composite fermion theory for the fractional quantum Hall effect. The goal of this perspective article is to note that they subscribe to a common underlying paradigm: They both connect these exotic quantum liquids to certain ordinary Fermi liquids residing in unphysical Hilbert spaces. Such a relation yields numerous nontrivial experimental consequences, exposing these theories to rigorous and definitive tests.

Bose fluids above T(c): incompressible vortex fluids and "supersolidity".

This Letter emphasizes that nonlinear rotational or diamagnetic susceptibility is characteristic of Bose fluids above their superfluid T(C)'s. For sufficiently slow rotation or, for superconductors, weak B fields, this amounts to an incompressible response to vorticity. The cause is that there are terms missing in the conventionally accepted model Hamiltonian for quantized vortices in the Bose fluid. The resulting susceptibility can account for recent observations of Chan et al. [Nature (London) 427, 225 (2004); Science 305, 1941 (2004)] on solid He and Ong et al. [Europhys. Lett. 72, 451 (2005) on cuprate superconductors.

Determining the underlying Fermi surface of strongly correlated superconductors.

The notion of a Fermi surface (FS) is one of the most ingenious concepts developed by solid-state physicists during the past century. It plays a central role in our understanding of interacting electron systems. Extraordinary efforts have been undertaken, by both experiment and theory, to reveal the FS of the high-temperature superconductors, the most prominent class of strongly correlated superconductors. Here, we discuss some of the prevalent methods used to determine the FS and show that they generally lead to erroneous results close to half-filling and at low temperatures, because of the large superconducting gap (pseudogap) below (above) the superconducting transition temperature. Our findings provide a perspective on the interplay between strong correlations and superconductivity and highlight the importance of strong coupling theories for the characterization and determination of the underlying FS in angle-resolved photoemission spectroscopy experiments.

Electronic structure of strongly correlated d-wave superconductors.

We study the electronic structure of a strongly correlated d-wave superconducting state. Combining a renormalized mean field theory with direct calculation of matrix elements, we obtain explicit analytical results for the nodal Fermi velocity upsilon(F), the Fermi wave vector k(F), and the momentum distribution n(k) as a function of hole doping in a Gutzwiller projected d-wave superconductor. We calculate the energy dispersion E(k) and spectral weight of the Gutzwiller-Bogoliubov quasiparticles and find that the spectral weight associated with the quasiparticle excitation at the antinodal point shows a nonmonotonic behavior as a function of doping. Results are compared to angle resolved photoemission spectroscopy of the high-temperature superconductors.

Physics of the resonating valence bond (pseudogap) state of the doped mott insulator: spin-charge locking.

The properties of the pseudogap phase above T(C) of the high-T(C) cuprate superconductors are described by showing that the Anderson-Nambu SU(2) spinors of a resonating valence bond spin gap "lock" to those of the electron charge system because of the resulting improvement of kinetic energy. This enormously extends the range of the vortex liquid state in these materials. A heuristic description of the nonlocal electrodynamics of this pseudogap-vortex liquid state is proposed.

Thermodynamics of an incommensurate quantum crystal.

We present a theory of the thermodynamics of an incommensurate quantum solid. The ground state of the solid is assumed to be an incommensurate crystal, with quantum zero-point vacancies and interstitials and thus a non-integer number of atoms per unit cell. We show that at low temperature T, the variation of the net vacancy concentration should be as T4 and that the first correction to the specific heat due to this varies as T7; these are quite consistent with experiments on solid helium-4. We also make some observations about the recent experimental reports of "supersolidity" in solid helium-4 that motivate a renewed interest in quantum crystals.

Effect of raloxifene on serum triglycerides in postmenopausal women: influence of predisposing factors for hypertriglyceridemia.

BACKGROUND: Estrogen increases serum triglyceride (TG) levels and induces hypertriglyceridemia in susceptible women. The effect of raloxifene (RLX), a selective estrogen-receptor modulator, on serum TG has not been studied in detail. OBJECTIVE: The purpose of this study was to examine the effect of RLX on serum TG levels in postmenopausal women with and without osteoporosis, including those with predisposing factors for hypertriglyceridemia. METHODS: Fasting serum TG levels were assessed over 36 months in 2738 osteoporotic postmenopausal women (mean age, 67 years) assigned to placebo or RLX (60 or 120 mg/d) in an osteoporosis treatment trial and over 24 months in 1318 postmenopausal women without osteoporosis (mean age, 54 years) assigned to placebo or RLX (60 or 150 mg/d) in 3 osteoporosis prevention trials. RESULTS: In the osteoporosis treatment trial, the median serum TG concentration decreased in all groups, but significantly more in the placebo group (placebo, -3.4%; RLX 60 mg/d, -1.4%; RLX 120 mg/d, -1.3%; P = 0.002). In the osteoporosis prevention trials, the percentage change in median serum TG concentration was not significantly different among treatments (P = 0.22). Among women with varying degrees of hypertriglyceridemia at baseline (>2.82, >3.39, and >4.51 mmol/L), the median serum TG level at the end of the study decreased from baseline in all groups, with no significant differences among treatments (P > or = 0.13). The effect of RLX on serum TG level was not influenced by age, smoking status, use of alcohol, or presence of diabetes (P > or = 0.10 for all interactions). Among women in the highest tertile of body mass index (>26.4 kg/m2), RLX increased serum TG levels significantly compared with placebo (placebo, -3%; RLX 60 mg/d, 6%: RLX 120 mg/d, 4%; P < 0.05); the absolute increase from baseline with RLX in this subgroup was 0.05 mmol/L (4.4 mg/dL). CONCLUSIONS: RLX did not increase serum TG in postmenopausal women overall or among women with elevated TG levels or evidence of diabetes at baseline. TG levels increased slightly but statistically significantly in women in the upper tertile of body mass index who were treated with RLX.

Design and methods of the Raloxifene Use for The Heart (RUTH) study.

Raloxifene is a selective estrogen receptor modulator that lowers total and low-density lipoprotein (LDL) cholesterol, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. The Raloxifene Use for The Heart (RUTH) trial is designed to determine whether raloxifene 60 mg/day compared with placebo: (1) lowers the risk of the coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI); and (2) reduces the risk of invasive breast cancer in women at risk for a major coronary event. RUTH is a double-blind, placebo-controlled, randomized clinical trial of 10,101 postmenopausal women aged > or =55 years from 26 countries. Women are eligible for randomization if they are postmenopausal and have documented coronary heart disease (CHD), peripheral arterial disease, or multiple risk factors for CHD. Use of estrogen within the previous 6 months is an exclusion factor. The study will be terminated after a minimum of 1,670 participants experience a primary coronary end point. Secondary end points include cardiovascular death, myocardial revascularization, noncoronary arterial revascularization, stroke, all-cause hospitalization, all-cause mortality, all breast cancers, clinical fractures, and venous thromboembolic events, in addition to the individual components of the composite primary coronary end point. RUTH will provide important information about the risk-benefit ratio of raloxifene in preventing acute coronary events and invasive breast cancer, as well as information about the natural history of CHD in women at risk of major coronary events.

Effects of raloxifene and hormone replacement therapy on markers of serum atherogenicity in healthy postmenopausal women.

OBJECTIVE: To determine the effect of raloxifene (RLX) and hormone replacement therapy (HRT) on non-high density lipoprotein cholesterol (non-HDL-C) levels and the apolipoprotein-B/apolipoprotein-A1 (apo-B/apo-A1) concentration ratio, markers of serum atherogenicity, in postmenopausal women. METHODS: Three hundred and ninety healthy postmenopausal women aged 45-72 years were enrolled in a double-blind, randomized, placebo-controlled, parallel trial at eight outpatient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), 60 or 120 mg/day raloxifene, or placebo for 6 months. Serum concentrations of non-HDL cholesterol and the apo-B/apo-A1 concentration ratio were measured in serum samples obtained at baseline and at 6 months of treatment. RESULTS: At 6 months, non-HDL-C and apo-B/apo-A1 were significantly reduced by 60 mg/day RLX (10 and 11%, respectively), 120 mg/day RLX (9 and 12%, respectively) and HRT (10 and 12%, respectively), compared with placebo. The effect of all treatments to lower non-HDL-C and apo-B/apo-A1 was greatest in women with hypercholesterolemia (total-C>240 mg/dl) at baseline. Among women with undesirable (>160 mg/dl) non-HDL cholesterol at baseline, RLX and HRT lowered the percentage of these women remaining above this threshold after 6 months (placebo, 89%; 60 mg/day RLX, 61%; 120 mg/day RLX, 74%; HRT, 58%). Similar results were observed for women with high (>190 mg/dl) non-HDL cholesterol at baseline. CONCLUSION: In healthy postmenopausal women, RLX and HRT lower serum non-HDL-C and apo-B/apo-A1, indicators of serum atherogenicity, to a similar extent.

Monoclonal antibodies specific for Neisseria meningitidis group B polysaccharide and their peptide mimotopes.

From five mice immunized with Escherichia coli K1 bacteria, we produced 12 immunoglobulin M hybridomas secreting monoclonal antibodies (MAbs) that bind to Neisseria meningitidis group B (NMGB). The 12 MAbs also bound the capsular polysaccharide (PS) of E. coli K1 [which, like NMGB, is alpha(2-8)-linked polysialic acid (PSA)] and bound to EV36, a nonpathogenic E. coli K-12 strain producing alpha(2-8) PSA. Except for HmenB5, which cross-reacted with N. meningitidis group C, none of the MAbs bound to N. meningitidis groups A, C, and Y. Of the 12 MAbs, 6 were autoantibodies as defined by binding to CHP-134, a neuroblastoma cell line expressing short-chain alpha(2-8) PSA; five of these MAbs killed NMGB in the presence of rabbit complement, and two also killed NMGB with human complement. The other six MAbs, however, were nonautoreactive; all killed NMGB with rabbit complement, and five killed NMGB with human complement. To obtain peptide mimotopes of NMGB PS, four of the nonautoreactive MAbs (HmenB2, HmenB3, HmenB13, and HmenB14) were used to screen two types of phage libraries, one with a linear peptide of 7 amino acids and the other with a circular peptide of 7 amino acids inserted between two linked cysteines. We obtained 86 phage clones that bound to the screening MAb in the absence but not in the presence of E. coli K1 PSA in solution. The clones contained 31 linear and 4 circular mimotopes expressing unique sequences. These mimotopes nonrandomly expressed amino acids and were different from previously described mimotopes for NMGB PS. The new mimotopes may be useful in producing a vaccine(s) capable of eliciting anti-NMGB antibodies not reactive with neuronal tissue.

Nature of spin excitations in two-dimensional mott insulators: undoped cuprates and other materials.

We investigate the excitation spectrum of a two-dimensional resonating valence bond (RVB) state. Treating the pi-flux phase with antiferromagnetic correlations as a variational ground state, we recover the long wavelength magnon as an "RVB exciton." However, this excitation does not exhaust the entire spectral weight and the high-energy spectrum is dominated by fermionic excitations. The latter can be observed directly by inelastic neutron scattering, and we predict their characteristic energy scales along different high symmetry directions in the magnetic Brillouin zone. We also interpret experimental results on two magnon Raman scattering and midinfrared absorption within this scenario.

Giant enhancement of the thermal Hall conductivity kappa(xy) in the superconductor YBa(2)Cu(3)O(7).

In high-purity YBa(2)Cu(3)O(7), the (weak-field) thermal Hall conductivity kappa(xy) is observed to increase a thousand-fold between 90 and 30 K. The inferred quasiparticle lifetime tau increases a hundred-fold starting below 90 K, in disagreement with a recent photoemission experiment. We show that kappa(xy) exhibits a specific scaling behavior below approximately 30 K. This scaling may bear on the issue of whether Landau quantization of the quasiparticle states occurs.

The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial.

C-Reactive protein and homocysteine are independent risk factors for the development of cardiovascular disease. This study compared the effects of hormone replacement therapy (HRT) and raloxifene on serum C-reactive protein and homocysteine levels as markers of cardiovascular risk in healthy postmenopausal women. Healthy postmenopausal women (n = 390) were enrolled in a double blind, randomized, placebo-controlled, 6-month trial at eight out-patient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), raloxifene (60 or 120 mg/day), or placebo for 6 months. C-Reactive protein and homocysteine were measured in baseline and 6-month serum samples. HRT increased C-reactive protein levels by 84% (P<0.001), whereas raloxifene (60 and 120 mg/day) had no significant effect (-6% and -4%;, respectively; P>0.2). Raloxifene (60 and 120 mg/day) significantly lowered serum levels ofhomocysteine by 8% (P = 0.014) and 6% (P = 0.024), respectively, similar to the 7% (P = 0.014) reduction obtained with HRT. We conclude that HRT and raloxifene lower serum homocysteine levels to a comparable extent in postmenopausal women. Whereas cardiovascular risk predicted by C-reactive protein in healthy postmenopausal women is not influenced by raloxifene, the relationship between elevated C-reactive protein levels with HRT and cardiovascular disease events requires further study.

Hormone and nonhormone therapy for the maintenance of postmenopausal health: the need for randomized controlled trials of estrogen and raloxifene.

Multiple health benefits have been postulated for the long-term use of hormone therapy in postmenopausal women, most notably for prevention of osteoporotic fractures and coronary heart disease, as well as several risks, including cancer of the breast and uterus and venous thromboembolism. Cardiovascular disease is the most common cause of death among postmenopausal women. If real, the reduction in risk of coronary heart disease by hormone use suggested by observational studies would likely outweigh the risks. The decision to initiate and maintain hormone therapy is complicated by uncertainties about estrogen's true benefits and risks. Raloxifene, a selective estrogen receptor modulator (SERM), appears to have many of the benefits of estrogen without the cancer risks. It is not known if SERMs can provide significant cardiovascular protection. This article reviews the relation of use of postmenopausal hormones and raloxifene to women's health and addresses the need for large randomized trials to quantify the effect of both postmenopausal estrogen and raloxifene on cardiovascular health.