A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients.

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

Statistical Physics of Viral Capsids with Broken Symmetry.

We present a model to understand quantitatively the role of symmetry breaking in assembly of macromolecular aggregates in general, and the protein shells of viruses in particular. A simple dodecahedral lattice model with a quadrupolar order parameter allows us to demonstrate how symmetry breaking may reduce the probability of assembly errors and, consequently, enhance assembly efficiency. We show that the ground state is characterized by large-scale cooperative zero-energy modes. In analogy with other models, this suggests a general physical principle: the tendency of biological molecules to generate symmetric structures competes with the tendency to break symmetry in order to achieve specific functional goals.

Elasticity theory of macromolecular aggregates.

We present a version of continuum elasticity theory applicable to aggregates of functional biomolecules at length scales comparable to that of the component molecules. Unlike classical elasticity theory, the stress and strain fields have mathematical discontinuities along the interfaces of the macromolecules, due to conformational incompatibility and large scale conformational transitions. The method is applied to the P-II to EI shape transition of the protein shell of the virus HK97. We show that protein residual stresses generated by incompatibility drive a "reverse buckling" transition from an icosahedral to a dodecahedral shape via a "critical" spherical shape, which can be identified as the P-II state.

The shapes and sizes of closed, pressurized random walks.

Two-dimensional cell-like membranes acted on by osmotic pressure differentials are represented by closed, unrestricted random walks. The treatment omits excluded-volume effects, and the pressure that is imposed thus favors an oriented area, so that the shriveled configuration of a vesicle with excess external pressure is inaccessible in this model. Nevertheless, the approach has the decided advantage of yielding analytic expressions in a complete statistical analysis. Results are presented for the average square of the radius of gyration, the asphericity, and the probability distribution of the principal components of the radius of gyration tensor. The analysis is done in both the constant-pressure and constant-area ensembles.

The shapes of random walks.

A theoretical description of the shape of a random object is presented that is analytically simple in application but quantitatively accurate. The asymmetry of the object is characterized in terms of the invariants of a tensor, analogous to the moment-of-inertia tensor, whose eigenvalues are the squares of the principal radii of gyration. The complications accompanying ensemble averaging because of random processes are greatly reduced when the object is embedded in a space of high dimensionality, d. Exact analytical expressions are presented in the case of infinite spatial dimensions, and a procedure for developing an expansion in powers of l/d is discussed for linear chain and ring-type random walks. The first two terms in such an expansion lead to results for various shape parameters that agree remarkably well with those calculated by computer simulation. The method can be extended to yield an approximate, but extremely accurate, expression for the probability distribution function directly. The theoretical approach discussed here can, in principle, be used to describe the shape of other random fractal objects as well.

Growth and erosion of thin solid films.

Thin films that are grown by the process of sputtering are, by and large, quite unlike the smooth, featureless structures that one might expect. In general, these films have a complicated surface morphology and an extended network of grooves and voids in their interiors. Such features can have a profound effect on the physical properties of a thin film. The surface irregularities and the bulk defects are the result of a growth instability due to competitive shadowing, an effect that also plays a role in geological processes such as erosion. For amorphous thin films, the shadow instability can be described by a remarkably simple model, which can be shown to reproduce many important observed characteristics of thin film morphology.

Smectic viral capsids and the aneurysm instability.

The capsids of certain Archaea-infecting viruses undergo large shape changes, while maintaining their integrity against rupture by osmotic pressure. We propose that these capsids are in a smectic liquid crystalline state, with the capsid proteins assembling along spirals. We show that smectic capsids are intrinsically stabilized against the formation of localized bulges with non-zero Gauss curvature while still allowing for large-scale cooperative shape transformation that involves global changes in the Gauss curvature.

Useful scars: Physics of the capsids of archaeal viruses.

We propose a physical model for the capsids of tailed archaeal viruses as viscoelastic membranes under tension. The fluidity is generated by thermal motion of scarlike structures that are an intrinsic feature of the ground state of large particle arrays covering surfaces with nonzero Gauss curvature. The tension is generated by a combination of the osmotic pressure of the enclosed genome and an extension force generated by filamentous structure formation that drives the formation of the tails. In continuum theory, the capsid has the shape of a surface of constant mean curvature: an unduloid. Particle arrays covering unduloids are shown to exhibit pronounced subdiffusive and diffusive single-particle transport at temperatures that are well below the melting temperature of defect-free particle arrays on a surface with zero Gauss curvature.

Are US hospitals making progress in implementing guidelines for prevention of Mycobacterium tuberculosis transmission?

BACKGROUND: Outbreaks of tuberculosis (TB) in hospitals have occurred when the Centers for Disease Control and Prevention (CDC) guideline recommendations for preventing the transmission of Mycobacterium tuberculosis were not fully implemented. OBJECTIVE: To determine whether US hospitals are making progress in implementing the CDC guidelines for preventing TB. METHODS: In 1992, we surveyed all public (city, county, Veterans Affairs, and primary medical school-affiliated) US hospitals (n = 632) and 444 (20%) random samples of all private hospitals with 100 beds or more. In 1996, we resurveyed 136 random samples (50%) of all 1992 respondent hospitals with 6 or more TB admissions in 1991. RESULTS: Of the 1076 hospitals surveyed in 1992, 763 (71%) respondents returned a completed questionnaire. Among these, 536 (71%) of 755 reported having rooms that met CDC criteria for acid-fast bacilli isolation, ie, negative air pressure, 6 or more air exchanges per hour, and air directly vented to the outside. The predominant respiratory protective device for health care workers was nonfitted surgical mask and attending physicians were infrequently (50%) included in tuberculin skin-testing programs. In the 1996 resurvey, 103 (76%) of 136 respondents returned a completed questionnaire. Of these, 99 (96%) reported having rooms that met CDC criteria for acid-fast bacilli isolation. The N95 respiratory protective devices were predominantly used by health care workers, and attending physicians were increasingly (69%) included in the hospitals' tuberculin skin-testing programs. CONCLUSIONS: Most US hospitals are making progress in the implementation of CDC guidelines for preventing the transmission of M tuberculosis.

Gram-negative bacteremia in open-heart-surgery patients traced to probable tap-water contamination of pressure-monitoring equipment.

OBJECTIVE: To determine the cause(s) of an outbreak of gram-negative bacteremia (GNB) in open-heart-surgery (OHS) patients at hospital A. DESIGN: Case-control and cohort studies and an environmental survey. RESULTS: Nine patients developed GNB with Enterobacter cloacae (6), Pseudomonas aeruginosa (5), Klebsiella pneumoniae (3), Serratia marcescens (2), or Klebsiella oxytoca (1) following OHS; five of nine patients had polymicrobial bacteremia. When the GNB patients were compared with randomly selected OHS patients, having had the first procedure of the day (8 of 9 versus 12 of 27, P = .02), longer cardiopulmonary bypass (median, 122 versus 83 minutes, P = .01) or cross-clamp times (median, 75 versus 42 minutes, P = .008), intraoperative dopamine infusion (9 of 9 versus 15 of 27, P = .01), or exposure to scrub nurse 6 (6 of 9 versus 4 of 27, P = .001) were identified as risk factors. When stratified by length of the procedure, only being the first procedure of the day and exposure to scrub nurse 6 remained significant. First procedures used pressure-monitoring equipment that was assembled before surgery and left open and uncovered overnight in the operating room, whereas other procedures used pressure-monitoring equipment assembled immediately before the procedure. At night, operating rooms were cleaned by maintenance personnel who used a disinfectant-water solution sprayed through a hose connected to an automatic diluting system. Observation of the use of this hose documented that this solution could have contacted and entered uncovered pressure-monitoring equipment left in the operating room. Water samples from the hose revealed no disinfectant, but grew P aeruginosa. The outbreak was terminated by setting up pressure-monitoring equipment immediately before the procedure and discontinuing use of the hose-disinfectant system. CONCLUSIONS: This outbreak most likely resulted from contamination of uncovered preassembled pressure-monitoring equipment by water from a malfunctioning spray disinfectant device. Pressure-monitoring equipment should be assembled immediately before use and protected from possible environmental contamination.

Constraints, histones, and the 30-nm spiral.

We investigate the mechanical stability of a segment of DNA wrapped around a histone in the nucleosome configuration, under the assumption that the proper model for this packaging arrangement is that of an elastic rod that is free to twist and that writhes subject to mechanical constraints. We find that the number of constraints required to stabilize the nuclesome configuration is determined by the length of the segment, the number of times the DNA wraps around the histone spool, and the specific constraints utilized. While it can be shown that four constraints suffice, in principle, to insure stability of the nucleosome, a proper choice must be made to guarantee the effectiveness of this minimal number. The optimal choice of constraints appears to bear a relation to the existence of a spiral ridge on the surface of the histone octamer. The particular configuration that we investigate is related to the 30-nm spiral, a higher-order organization of DNA in chromatin.

Crossover behavior in the isothermal susceptibility near the 3He critical point.

We present high-resolution measurements of the isothermal susceptibility of pure 3He near the liquid-gas critical point. PVT measurements were performed in the single-phase region over the reduced temperature range 3 x 10(-5)

[Leakage correction by resection of the deep dorsal penis vein. Assessment of results after 4 years of venous potency surgery]. / "Leakage"-Korrektur durch Resektion der Vena dorsalis penis profunda. Bestandsaufnahme nach 4 Jahren venöser Potenzchirurgie.

Resection of the deep dorsal vein is accepted as a short-term working procedure to reestablish erection in patients suffering from venous leakage. After 4 years with a standardized diagnostic and surgical program for pathologic venous drainage, we are now able to describe the outcome of vein resection in 51 men, whom we have treated 1-4 years before follow-up examination. After a median follow-up of 20 months, long-lasting full erection can be reported in 28 men. Of the remaining 23 men, reestablished erectile function decreased within 1 year in 8, while the operation failed in 15. Whereas the site of pathologic venous drainage and preoperative maintenance flow rates do not influence surgical outcome, a moderate arterial cofactor has become obvious in a large proportion of the unsuccessfully treated cases. In 14 of these men, papaverine testing has now become positive, so that penile self-injection of the drug makes adequate sexual intercourse possible. All patients with a postoperative negative papaverine reaction again have all the signs of a persistent pathological venous drainage; only in 2 of these cases has an ectopic vein been successfully resected.

[Pharmaco-cavernosonography and cavernosometry with a new roller pump (AP 300 C)]. / Pharmakokavernosographie und Kavernosometrie mit einer neuen Rollenpumpe (AP 300 C).

The paper gives a report on the first roller pump (AP 300 C) to be serially produced and approved by the Technical Control Board (Technischer Uberwachungsverein, TUV) for cavernosometry and pharmacocavernosography, and on preliminary experience with its use.

A process and considerations for activating a quality/productivity monitoring system.

In response to demands for cost containment in operational areas without subsequent declines in quality, many hospitals are implementing quality and productivity monitoring systems. This article describes the process used by St. Elizabeth Hospital Medical Center (SEHMC), Youngstown, Ohio, to determine that it would use an outside consultant, select a consultant, negotiate the contract and implement the program. The article offers practical advice for other hospitals considering using outside services for developing quality/productivity monitoring systems as well as other projects.

The direct effect of health managers on quality control, assessment, assurance.

In the midst of the many changes that are occurring in the health industry, the pursuit of quality remains a constant. In the past, efforts at quality control have largely focused on the provision of clinical care. In this article, the authors discuss the role of health managers in the provision of quality care beyond the clinical environment in the area of guest services. Additionally, they review how to improve the organizational climate in which services are provided and measure the results.

Hospital layoffs. One facility's experience with a work force reduction.

In 1994 the conversion of Tennessee's Medicaid program to managed care sharply reduced the census of all Memphis hospitals, including St. Joseph Hospital and Health Care Centers. St. Joseph's Operations Leadership group (OLG) decided that expenditures must be cut by $8 million-$6 million of it coming from wages and salaries--so the hospital could enter fiscal year 1995 with a balanced budget. With the help of a consulting firm, the OLG determined that the wage and salary cuts could be realized by laying off a certain number of employees. All workers were told, in a series of round-the-clock meetings, that 162 jobs (22 managers and 140 hourly workers) would be eliminated in nine days. The hospital's labor relations attorney approved the criteria according to which workers would be dismissed. On the designated days (one for managers, another for rank-and-file workers), the layoffs were completed in an organized manner. The OLG had arranged with a private firm to set up a career placement center for the dismissed employees. Of the 162, 105 took advantage of the center's services. Thirty-five of those (21 percent) had new jobs within 45 days of the layoffs. The OLG was straightforward with the local media about the layoffs. Hospital leaders calmed remaining St. Joseph workers' anxieties with a series of follow-up meetings. These sessions also provided the OLG with useful feedback on the way it had conducted the layoffs.