The design and conduct of clinical trials to limit missing data.

This article summarizes recommendations on the design and conduct of clinical trials of a National Research Council study on missing data in clinical trials. Key findings of the study are that (a) substantial missing data is a serious problem that undermines the scientific credibility of causal conclusions from clinical trials; (b) the assumption that analysis methods can compensate for substantial missing data is not justified; hence (c) clinical trial design, including the choice of key causal estimands, the target population, and the length of the study, should include limiting missing data as one of its goals; (d) missing-data procedures should be discussed explicitly in the clinical trial protocol; (e) clinical trial conduct should take steps to limit the extent of missing data; (f) there is no universal method for handling missing data in the analysis of clinical trials - methods should be justified on the plausibility of the underlying scientific assumptions; and (g) when alternative assumptions are plausible, sensitivity analysis should be conducted to assess robustness of findings to these alternatives. This article focuses on the panel's recommendations on the design and conduct of clinical trials to limit missing data. A companion paper addresses the panel's findings on analysis methods.

Predicting new solids and superconductors.

It is now possible to start with a simple model of a solid composed of atomic cores and itinerant valence electrons and compute the total energy for a given structural arrangement of atoms with enough precision to predict the existence of new solids and their properties. The application of the model based on the pseudopotential method is described with silicon chosen as a prototype material. With only information about the constituent atoms, the electronic, structural, vibrational, and even superconducting properties of solids can be calculated from first principles. The successful predictions of superconductivity in highly condensed hexagonal silicon and the existence of new high-pressure semiconductor phases are highlighted. A discussion is presented of the use of the method to discover new stable or metastable solids at high pressures.

Epidemiology of drug resistance: implications for a post-antimicrobial era.

In the last several years, the frequency and spectrum of antimicrobial-resistant infections have increased in both the hospital and the community. Certain infections that are essentially untreatable have begun to occur as epidemics both in the developing world and in institutional settings in the United States. The increasing frequency of drug resistance has been attributed to combinations of microbial characteristics, selective pressures of antimicrobial use, and societal and technologic changes that enhance the transmission of drug-resistant organisms. Antimicrobial resistance is resulting in increased morbidity, mortality, and health-care costs. Prevention and control of these infections will require new antimicrobial agents, prudent use of existing agents, new vaccines, and enhanced public health efforts to reduce transmission.

Protein antigens from Staphylococcus aureus strains associated with toxic-shock syndrome.

Staphylococcus aureus isolates from patients with toxic-shock syndrome have two antigenic proteins that distinguish these strains from isolates obtained from patients who do not have this syndrome and who are colonized or infected with S. aureus. These proteins may either represent antigenic markers, the toxin (or toxins), or toxic subunits that cause the clinical manifestations of this disease.

Drug-resistant Salmonella in the United States: an epidemiologic perspective.

Salmonellosis poses a health problem of large proportions in the United States. Annually, it accounts for more than 40,000 reported cases, 500 deaths, and financial costs well in excess of $50 million. Antimicrobial resistance is increasing in Salmonella strains, a finding that has important public health implications. Although the chain of transmission of the bacteria is often complex, combined epidemiologic and laboratory studies with the use of new methods in molecular biology make it possible to trace antimicrobial-resistant salmonellae to their primary source--foods of animal origin. These studies suggest that the antimicrobial drugs to which food animals are exposed provide selective pressure that leads to the appearance and persistence of resistant strains.

Prediction of new low compressibility solids.

An empirical model and an ab initio calculation of the bulk moduli for covalent solids are used to suggest possible new hard materials. The empirical model indicates that hypothetical covalent solids formed between carbon and nitrogen are good candidates for extreme hardness. A prototype system is chosen and a first principles pseudopotential total energy calculation on the system is performed. The results are consistent with the empirical model and show that materials like the prototype can have bulk moduli comparable to or greater than diamond. It may be possible to synthesize such materials in the laboratory.

Animal-to-man transmission of antimicrobial-resistant Salmonella: investigations of U.S. outbreaks, 1971-1983.

The importance and origin of antimicrobial-resistant Salmonella infections were examined in 52 outbreaks investigated by the Centers for Disease Control between 1971 and 1983. The case fatality rate was higher for patients infected with antimicrobial-resistant Salmonella (4.2 percent) than for those with antimicrobial-sensitive infections (0.2 percent). In the 38 outbreaks with identified sources, food animals were the source of 11 (69 percent) of 16 resistant and 6 (46 percent) of 13 sensitive outbreak strains.

Boron nitride nanotubes.

The successful synthesis of pure boron nitride (BN) nanotubes is reported here. Multi-walled tubes with inner diameters on the order of 1 to 3 nanometers and with lengths up to 200 nanometers were produced in a carbon-free plasma discharge between a BN-packed tungsten rod and a cooled copper electrode. Electron energy-loss spectroscopy on individual tubes yielded B:N ratios of approximately 1, which is consistent with theoretical predictions of stable BN tube structures.

Ultrahigh-pressure melting of lead: a multidisciplinary study.

Measurements of the melting temperature of lead, carried out to pressures of 1 megabar (10(11) pascal) and temperatures near 4000 kelvin by means of a laser-heated diamond cell, are in excellent agreement with the results of previous shock-wave experiments. The data are analyzed by means of first principles quantum mechanical calculations, and the agreement documents the reliability of current experimental and theoretical techniques for studies of melting at ultrahigh pressures. These studies have potentially wide-ranging applications, from planetary science to condensed matter physics.

Tuning High-Tc Superconductors via Multistage Intercalation.

Multistage intercalation has been used to tune the interaction between adjacent blocks of CuO(2) sheets in the bigh-T(c) (high superconducting transition temperature) superconductor Bi(2)Sr(2)CaCu(2)Ox. As revealed by atomic-resolution transmission electron microscopy images, foreign iodine atoms are intercalated into every nth BiO bilayer of the host crystal, resulting in structures of stoichiometry IBi2nSr2nCanCu2nOx with stage index n up to 4. An expansion of 3.6 angstroms for each intercalated BiO bilayer decouples the CuO(2) sheets in adjacent blocks. A comparison of the superconducting transition temperatures of the pristine host material and intercalated compounds of different stages suggests that the coupling between each pair of adjacent blocks contributes approximately 5 K to T(c) in Bi(2)Sr(2)CaCu(2)Ox.

Synthesis and Electronic Transport of Single Crystal K3C60.

Sizable single crystals of C(6O) have been synthesized and doped with potassium. Above the superconducting transition temperature T(c), the electrical resistivity p(T) displays a classic metal-like temperature dependence. The transition to the superconducting state at T(c) = 19.8 K is extremely sharp, with a transition width DeltaT < 200 mK. In contrast to transport behavior of doped polycrystalline and granular thin films, no anomalous fluctuations are observed near T(c) in single crystal specimens.

Amyloid protein precursor messenger RNAs: differential expression in Alzheimer's disease.

In situ hybridization was used to assess total amyloid protein precursor (APP) messenger RNA and the subset of APP mRNA containing the Kunitz protease inhibitor (KPI) insert in 11 Alzheimer's disease (AD) and 7 control brains. In AD, a significant twofold increase was observed in total APP mRNA in nucleus basalis and locus ceruleus neurons but not in hippocampal subicular neurons, neurons of the basis pontis, or occipital cortical neurons. The increase in total APP mRNA in locus ceruleus and nucleus basalis neurons was due exclusively to an increase in APP mRNA lacking the KPI domain. These findings suggest that increased production of APP lacking the KPI domain in nucleus basalis and locus ceruleus neurons may play an important role in the deposition of cerebral amyloid that occurs in AD.

Neuronal binucleation in Alzheimer disease hippocampus.

AIMS: The literature and teachings instruct that neurones in the adult brain are fully differentiated, quiescent cells that never divide. Somewhat surprisingly, and counter to such dogma, susceptible neurones in Alzheimer disease display an activated cell cycle phenotype. However, whether this leads to a coordinated procession through the cell cycle is unclear, particularly whether neurones enter anaphase and beyond. To begin to address this issue, in this study we sought to determine whether nuclear division occurs in these neurones. METHODS: We examined a series of 101 archived, routinely stained hippocampal sections collected at post mortem for neuropathological evaluation for evidence of neuronal binucleation. RESULTS: We report for the first time, binucleated neurones within the hippocampus in cases of Alzheimer disease but not in control cases (P < 0.05). CONCLUSIONS: While a relatively rare event, occurring once every 20,000 neurones, this morphological evidence that neuronal cells within the cortical regions of the adult human brain in Alzheimer disease contain two nuclei supports the hypothesis that neuronal cells can re-enter into a coordinated cell cycle that culminates in nuclear division.

Neuronal growth cone collapse triggers lateral extensions along trailing axons.

Axonal outgrowth is generally thought to be controlled by direct interaction of the lead growth cone with guidance cues, and, in trailing axons, by fasciculation with pioneer fibers. Responses of axons and growth cones were examined as cultured retinal ganglion cell (RGC) axons encountered repellent cues. Either contact with cells expressing ephrins or mechanical probing increased the probability of lead growth cone retraction. Lateral extension of filopodia and lamellipodia hundreds of microns behind the lead growth cone was correlated with its collapse. Transmission electron microscopy showed that some of the lateral extensions originate from the pioneer axon, whereas others represent growth cones of defasciculating trailing axons.

Antimicrobial resistance: prognosis for public health.

Antimicrobial resistance poses a significant threat to public health worldwide, with certain infections already being untreatable with antibiotics. Increasing resistance is resulting from antimicrobial use coupled with various epidemiological factors that enhance transmission of drug-resistant organisms, and the problem is likely to worsen. Control of antimicrobial resistance is feasible, but will be difficult.

Cardiac tamponade by loculated pericardial hematoma: limitations of M-mode echocardiography.

Three patients developed cardiac tamponade after heart surgery. Pericardial effusion was not identified by M-mode echocardiography. Two patients underwent two-dimensional echocardiography which showed compression of the right atrium by a localized mass. At reoperation, atrial compression by a loculated effusion or hematoma was found and successfully relieved. When cardiac tamponade is suggested by the clinical setting, but not supported by M-mode echocardiography, the presence of a loculated effusion should be considered and evaluated by a two-dimensional echocardiographic study.

Diastolic atrial compression: a sensitive echocardiographic sign of cardiac tamponade.

Nine patients with clinical and hemodynamic evidence of cardiac tamponade underwent M-mode and two-dimensional echocardiography. Pericardial effusion was documented in each patient. Four patients demonstrated respiratory variation in ventricular volumes in association with paradoxical pulse. Right ventricular compression was present in seven. In five patients, echocardiography demonstrated diastolic left atrial compression. In all nine patients, the apical four chamber view revealed diastolic right atrial compression. Drainage of 450 to 1,800 cc of pericardial fluid relieved the cardiac tamponade and eliminated the echocardiographic findings associated with this disorder. These observations suggest that the echocardiographic findings of atrial compression is a sensitive sign of cardiac tamponade.

Sterile, caseous mitral anular abscess.

Echocardiography identified three patients with a mitral anular mass. Fluoroscopy demonstrated a faint, homogeneous intracardiac calcific density in each patient. Cardiac catheterization and angiography were performed and showed no left ventricular inflow or outflow obstruction. One patient died suddenly and two patients had cardiac surgery (one for mitral regurgitation and another for constrictive pericarditis). Examination demonstrated that each mass was nonencapsulated, sterile and acellular and contained cholesterol, calcium and fatty acids. The clinical significance and cause of these masses are unclear at present.

Left ventricular outflow obstruction: a complication of mitral valvuloplasty.

Thirty-two patients with severe mitral regurgitation underwent Carpentier mitral valvuloplasty. Postoperatively, three of these patients developed clinical and echocardiographic evidence of left ventricular outflow tract obstruction. None of these patients had asymmetric septal hypertrophy or preoperative echocardiographic demonstration of systolic anterior motion of the mitral valve. Outflow obstruction postoperatively was caused by systolic anterior motion of the mitral valve. Because this potential complication of Carpentier mitral valvuloplasty produced significant hemodynamic effects in two patients, echocardiography should be routinely performed after this operation.

Measurement of the thermal properties of human skin. A review.

The effective use of techniques to detect and interpret surface and subsurface temperature patterns depends upon the thermal and electromagnetic properties of the tissues under examination. A review is made of the existent data concerned with the thermal characteristics of skin. The thermal conductivity, k, and thermal inertia, kpc, as measured as a function of local temperature are presented. The radiation properties of the skin are presented as a function of wavelength. It is concluded that the information currently available about the thermal properties and their normal variation with body site, skin color, and age is quite limited.