David B. Nash Advocates Better Outcomes And Lower Costs Through Population Health.

As interest grows in the potential impact of population health strategies, a recognized leader in the field-the founding dean of the Jefferson College of Population Health-explains key concepts and the role for this approach in safety, efficacy, and costs.

Seeking Solutions to the Opioid Crisis.

At an event focusing on population-health approaches to the opioid epidemic, discussants agreed that better coordination of care, community involvement in finding solutions, and more consistent use of improved pain-control options are required.

A P&T Snapshot of the Nation's Progress Against Cancer.

Although the death rate from cancer has fallen in recent years, progress against these diseases is uneven. This issue focuses on research efforts to find treatments.

Selective probing of photoinduced charge and spin dynamics in the bulk and surface of a topological insulator.

Topological insulators possess completely different spin-orbit coupled bulk and surface electronic spectra that are each predicted to exhibit exotic responses to light. Here we report time-resolved fundamental and second harmonic optical pump-probe measurements on the topological insulator Bi(2)Se(3) to independently measure its photoinduced charge and spin dynamics with bulk and surface selectivity. Our results show that a transient net spin density can be optically induced in both the bulk and surface, which may drive spin transport in topological insulators. By utilizing a novel rotational anisotropy analysis we are able to separately resolve the spin depolarization, intraband cooling, and interband recombination processes following photoexcitation, which reveal that spin and charge degrees of freedom relax on very different time scales owing to strong spin-orbit coupling.

Nonlinear optical probe of tunable surface electrons on a topological insulator.

We use ultrafast laser pulses to experimentally demonstrate that the second-order optical response of bulk single crystals of the topological insulator Bi(2)Se(3) is sensitive to its surface electrons. By performing surface doping dependence measurements as a function of photon polarization and sample orientation we show that second harmonic generation can simultaneously probe both the surface crystalline structure and the surface charge of Bi(2)Se(3). Furthermore, we find that second harmonic generation using circularly polarized photons reveals the time-reversal symmetry properties of the system and is surprisingly robust against surface charging, which makes it a promising tool for spectroscopic studies of topological surfaces and buried interfaces.

Light-induced anomalous Hall effect in graphene.

Many non-equilibrium phenomena have been discovered or predicted in optically-driven quantum solids1. Examples include light-induced superconductivity2,3 and Floquet-engineered topological phases4-8. These are short lived effects that should lead to measurable changes in electrical transport, which can be characterized using an ultrafast device architecture based on photoconductive switches9. Here, we report the observation of a light-induced anomalous Hall effect in monolayer graphene driven by a femtosecond pulse of circularly polarized light. The dependence of the effect on a gate potential used to tune the Fermi level reveals multiple features that reflect a Floquet-engineered topological band structure4,5, similar to the band structure originally proposed by Haldane10. This includes an approximately 60 meV wide conductance plateau centered at the Dirac point, where a gap of equal magnitude is predicted to open. We find that when the Fermi level lies within this plateau, the estimated anomalous Hall conductance saturates around 1.8±0.4 e2/h.

The pathogenesis of Shigella diarrhea. I. Enterotoxin production by Shigella dysenteriae I.

A strain of Shigella dysenteriae 1, freshly isolated from a patient with dysentery in Guatemala in August 1969, was found to elaborate an enterotoxin into the liquid of broth cultures. Partial purification of the enterotoxin by ultrafiltration on graded polymeric membranes and Sephadex gel filtration (Pharmacia Fine Chemicals, Inc., Piscataway, N. J.) suggested an approximate molecular weight of 55,000-60,000. The partially purified toxin was heat-labile, pronase sensitive, and activated by alkaline pH, and it elicited fluid production in ligated rabbit ileal segments; it failed, however, to cause increased vascular permeability in skin. When the activities of equal weights of identically prepared Vibrio cholerae and S. dysenteriae enterotoxins were compared in the rabbit ileum the latter caused a significantly smaller volume response with increased concentrations of potassium, chloride, and protein. The previously described neurotoxic (mouse lethal) factor was also present and eluted from Sephadex G-150 with the enterotoxin. If these biological activities prove to be possessed by a single molecular species, it is suggested that it be renamed Shigella enterotoxin in recognition of the physiologically more relevant biological action.

Wrinkling of a bilayer membrane.

The buckling of elastic bodies is a common phenomenon in the mechanics of solids. Wrinkling of membranes can often be interpreted as buckling under constraints that prohibit large-amplitude deformation. We present a combination of analytic calculations, experiments, and simulations to understand wrinkling patterns generated in a bilayer membrane. The model membrane is composed of a flexible spherical shell that is under tension and that is circumscribed by a stiff, essentially incompressible strip with bending modulus B . When the tension is reduced sufficiently to a value sigma , the strip forms wrinkles with a uniform wavelength found theoretically and experimentally to be lambda=2pi(B/sigma)(1/3). Defects in this pattern appear for rapid changes in tension. Comparison between experiment and simulation further shows that, with larger reduction of tension, a second generation of wrinkles with longer wavelength appears only when B is sufficiently small.

Effects of transients in LIGO suspensions on searches for gravitational waves.

This paper presents an analysis of the transient behavior of the Advanced LIGO (Laser Interferometer Gravitational-wave Observatory) suspensions used to seismically isolate the optics. We have characterized the transients in the longitudinal motion of the quadruple suspensions during Advanced LIGO's first observing run. Propagation of transients between stages is consistent with modeled transfer functions, such that transient motion originating at the top of the suspension chain is significantly reduced in amplitude at the test mass. We find that there are transients seen by the longitudinal motion monitors of quadruple suspensions, but they are not significantly correlated with transient motion above the noise floor in the gravitational wave strain data, and therefore do not present a dominant source of background noise in the searches for transient gravitational wave signals. Using the suspension transfer functions, we compared the transients in a week of gravitational wave strain data with transients from a quadruple suspension. Of the strain transients between 10 and 60 Hz, 84% are loud enough that they would have appeared above the sensor noise in the top stage quadruple suspension monitors if they had originated at that stage at the same frequencies. We find no significant temporal correlation with the suspension transients in that stage, so we can rule out suspension motion originating at the top stage as the cause of those transients. However, only 3.2% of the gravitational wave strain transients are loud enough that they would have been seen by the second stage suspension sensors, and none of them are above the sensor noise levels of the penultimate stage. Therefore, we cannot eliminate the possibility of transient noise in the detectors originating in the intermediate stages of the suspension below the sensing noise.

Extension of host range of Rhizobium leguminosarum bv. trifolii caused by point mutations in nodD that result in alterations in regulatory function and recognition of inducer molecules.

The positive activation of several nodulation genes in strain ANU843 of Rhizobium leguminosarum biovar trifolii is mediated by the product of the nodD gene and by the interaction of NodD with plant-secreted inducer and anti-inducer compounds. We have mutagenized the nodD gene of strain ANU843 with nitrosoguanidine and have found that the ability of the mutated nodD products to interact with inducer and anti-inducer compounds is affected by the amino acid sequence in at least two key regions, including a novel area between amino acids 77 and 123. Several novel classes of mutants were recognized by phenotypic and molecular analysis of the mutant nodD genes. Classes 1 and 4 mutants were able to induce nodA expression independently of the addition of inducer and anti-inducer compounds and were unable to mediate autoregulation of the nodD gene. Classes 2 and 3 mutants retained several properties of the wild-type nodD, including the ability to interact with inducer and anti-inducer compounds and the capacity to autoregulate nodD expression. In addition, class 2 mutants showed an inducer-independent ability to mediate nodA expression to 10-fold higher levels over control strains. The class 3 mutant showed reactivity to compounds that had little or no inducing ability with the wild-type nodD. An alteration in NodD function was demonstrated with classes 2 and 3 mutants, which showed greatly enhanced ability to complement a Tn5-induced mutation in the nodD1 gene of strain NGR234 and to restore nodulation ability on the tropical legume siratro. Mutants of nodD possessing inducer-independent ability to activate nod gene expression (classes 1, 2, and 4) were capable of extending the host range of R. l. bv. trifolii to the nonlegume Parasponia. DNA sequence analysis showed that single base changes were responsible for the altered phenotypic properties of five of six mutants examined. Four of the six mutations affected amino acid residues in a putative receiver domain in the N-terminal end of the nodD protein.

Free-electron laser exploiting a superlattice-like medium.

Amplification in free-electron lasers exploiting media with periodically modulated refractive indices is studied in the regime of a large modulation. The conditions for realization of the large-modulation regime in a superlattice-like medium are established. The maximized gain, the corresponding saturation field and efficiency, as well as the optimal electron energy and propagation direction are determined. It is shown that the large-modulation regime makes it possible to extend significantly the operation frequency domain of the FEL employing a low-relativistic electron beam. Relationship with the Cherenkov and stimulated resonance-transition-radiation FELs is discussed. This research is partially supported by RFBR grant 97-02-17783.

Treatment of severe pertussis: a study of the safety and pharmacology of intravenous pertussis immunoglobulin.

BACKGROUND: Pertussis in infants is often severe, resulting in complications and prolonged hospitalization. Treatment is limited to supportive care. Antibiotics do not significantly alter the course of the disease. Therapies directed at pertussis toxin, a major virulence factor of Bordetella pertussis, might be beneficial. This study examines the safety and pharmacology of intravenous pertussis immunoglobulin (P-IGIV), which has high levels of pertussis toxin antibodies. METHODS: P-IGIV was prepared as a 4% IgG solution from the pooled plasma from donors immunized with inactivated pertussis toxoid. The IgG pertussis toxin antibody concentration of 733 microg/ml is >7-fold higher than contained in conventional intravenous immunoglobulin products. Children with presumptive pertussis were allocated to one of three treatment doses of P-IGIV. RESULTS: Twenty-six of 30 enrolled children had confirmed pertussis. There were no adverse events associated with P-IGIV except one patient who had transient hypotension that responded to an infusion rate decrease. P-IGIV doses of 1500, 750 and 250 mg/kg achieved > or =4-fold, 3-fold and >2-fold rises in peak geometric mean titers of pertussis toxin IgG antibodies, respectively. P-IGIV exhibited a half-life of 38.4 days and a volume of distribution of 87.8 ml/kg. All three treatment groups showed declines in lymphocytosis (P < 0.05) and paroxysmal coughing by the third day after P-IGIV infusion compared with preinfusion values. CONCLUSION: P-IGIV is safe and achieves high pertussis toxin antibody titers in infants. This study provides data for a prospective, controlled trial of P-IGIV.

The effect of prophylactic intravenous immune globulin on the incidence of septicemia in marrow transplant recipients.

Ninety-seven patients randomized to receive (45 patients) or not to receive (52 patients) intravenous cytomegalovirus immune globulin before and after allogeneic marrow transplantation were evaluated retrospectively for the occurrence of bacterial and fungal septicemia in the first 100 days post-transplant. In a proportional hazards regression test, infection prevention regimens, immunoglobulin administration, age and occurrence of acute graft-versus-host disease were tested simultaneously for the occurrence of septicemia in the pre- and post-engraftment period. Of these factors, only patients receiving immunoglobulin had significantly fewer episodes of septicemia following engraftment with 11 (26%) patients in the globulin group having 14 episodes compared to 22 (42%) patients in the control group having 27 episodes (p = 0.039). None of the patients experienced complications with the immunoglobulin infusions. These results suggest that the administration of intravenous immunoglobulin may be a practical and effective method to decrease the incidence of septicemia following marrow transplantation.

Metastatic hepatocellular carcinoma presenting as epidural hematoma: case report.

OBJECTIVE AND IMPORTANCE: A case of acutely symptomatic epidural hematoma caused by metastatic hepatocellular carcinoma (HCC) to the cranium is reported. This is a rare case of metastatic HCC without known primary presenting as an epidural hematoma. CLINICAL PRESENTATION: The patient presented with an acute onset of headache, aphasia, and right hemiparesis 2 weeks after he experienced minor trauma to the cranium. An emergency computed tomographic scan of the head revealed the presence of a left parietal epidural hematoma. INTERVENTION: An emergency evacuation of the epidural hematoma was performed, and metastatic HCC was diagnosed. CONCLUSION: The patient's neurological deficits were reversed with surgical intervention, and he is now undergoing palliative chemotherapy. This was the first clinical manifestation of HCC in this patient. This case reaffirms the neurosurgeon's role in the complex, multidisciplinary care of patients with craniospinal metastasis.

Formulation strategies for the stabilization of tetanus toxoid in poly(lactide-co-glycolide) microspheres.

The development of a single-dose tetanus vaccine based on Poly(Lactic acid) (PLA) or Poly(Lactide-co-Glycolide) (PLGA) microspheres has been complicated due to the instability of tetanus toxoid (TT) inside these systems. Herein we report an attempt to re-design PLGA microspheres by co-encapsulating TT in the dry solid state together with potential protein stabilizers, such as trehalose, bovine serum albumin, alginate, heparin, dextran or poloxamer 188 and by using an appropriate microencapsulation technique. These newly developed PLGA microspheres were able to release in vitro antigenically active TT for at least 5 weeks, the amount released being highly dependent on the stabilizing excipient used. More specifically, results showed that dextran and heparin provided a particularly stabilizing environment for TT inside the microspheres during the polymer degradation process. The efficacy of this strategy was demonstrated by the high, long lasting titers of neutralizing antibodies achieved after in vivo administration of dextran-containing microspheres with a small amount of alum-adsorbed TT, as compared to the commercial adsorbable tetanus vaccine. These findings suggest that future developments in the area of vaccinology depend on ability to combine a detailed knowledge of the microencapsulation technology with a rational choice of stabilizing excipient or combination of excipients.

A molecular orbital study of a model of the Mg2+ coordination complex of the self splicing reaction of ribosomal RNA.

Recent discoveries have established the fact that RNA is capable of acting as an enzyme. In this study two different types of molecular orbital calculations, INDO and ab initio, were used in an attempt to assess the structural/functional role of the Mg2+ hydrated complex in ribozyme reactions. Preliminary studies indicate that the reaction is multistep and that the Mg2+ complex exerts a stabilizing effect on the intermediate or midpoint of the reaction.

Control over topological insulator photocurrents with light polarization.

Three-dimensional topological insulators represent a new quantum phase of matter with spin-polarized surface states that are protected from backscattering. The static electronic properties of these surface states have been comprehensively imaged by both photoemission and tunnelling spectroscopies. Theorists have proposed that topological surface states can also exhibit novel electronic responses to light, such as topological quantum phase transitions and spin-polarized electrical currents. However, the effects of optically driving a topological insulator out of equilibrium have remained largely unexplored experimentally, and no photocurrents have been measured. Here, we show that illuminating the topological insulator Bi(2)Se(3) with circularly polarized light generates a photocurrent that originates from topological helical Dirac fermions, and that reversing the helicity of the light reverses the direction of the photocurrent. We also observe a photocurrent that is controlled by the linear polarization of light and argue that it may also have a topological surface state origin. This approach may allow the probing of dynamic properties of topological insulators and lead to novel opto-spintronic devices.