Restraint and Seclusion Practices and Policies in U.S. Forensic Psychiatric Hospitals.

Over the last 30 years, there have been significant efforts to reduce the use of restraint and seclusion in psychiatric hospitals. Although authors have previously described restraint policies and practices in general psychiatry settings across the United States, this study is the first to attempt to describe policies regarding those practices in forensic hospital settings. We review the history of restraint and seclusion use in the United States, placing it within an international context. We then describe the results of a national survey of state forensic services directors regarding restraint modalities and policies in forensic hospital facilities. Twenty-nine respondents representing 25 states completed the survey. The results indicate that physical holds are the most frequently available method of restraint and that restraint chairs are the least frequently available. Most respondents reported having a policy regulating the use of restraint in their facilities, most commonly at the institutional level.

An Analysis of Risk-Assessment Driven Security Restraint Use during the Transport of Forensic Patients.

Transporting forensic psychiatric patients outside of forensic hospitals has significant risks that pose competing safety and patients' rights interests. Psychiatrists and hospital administrators have a duty to keep their staff and the community safe, but this must be carefully balanced with their obligation to uphold the civil rights and liberty interests of their patients. A critical decision in this balancing is whether to utilize security restraints during patient transportation. Addressing these competing interests while striving to safely transport forensic hospital patients to the community can be challenging as hospital staff and patient advocates may voice strong, and sometimes opposing, opinions about this debate. Very little research has been conducted about these high risk and often contentious actions. Here, we describe the process for assessing risk for violence, self-harm, and elopement prior to transportation at one state forensic hospital using a pretransport risk-assessment tool created specifically for that purpose. We then present the results of research identifying which clinical and legal factors identified by our risk-assessment tool correlate with patients being transported with restraints. We also evaluated the potential for racial/ethnic and gender biases in this transportation risk-assessment process.

Binding of antifusion peptides with HIVgp41 from molecular dynamics simulations: quantitative correlation with experiment.

Peptides based on C-terminal regions of the human immunodeficiency virus (HIV) viral protein gp41 represent an important new class of antiviral therapeutics called peptide fusion inhibitors. In this study, computational methods were used to model the binding of six peptides that contain residues that pack into a conserved hydrophobic pocket on HIVgp41, an attractive target site for the development of small molecule inhibitors. Free energies of binding were computed using molecular mechanics Generalized Born surface area (MM-GBSA) methods from molecular dynamics (MD) simulations, which employed either explicit (TIP3P) or continuum Generalized Born (GB) water models and strong correlations between experimental and computational affinities were obtained in both cases. Energy decomposition of the TIP3P-MD results (r2 = 0.75) reveals that variation in experimental affinity is highly correlated with changes in intermolecular van der Waals energies (deltaE(vdw)) on both a local (residue-based, r2 = 0.94) and global (peptide-based, r2 = 0.84) scale. The results show that differential association of C-peptides with HIVgp41 is driven solely by changes within the conserved pocket supporting the hypothesis that this region is an important drug target site. Such strong agreement with experiment is notable given the large size of the ligands (34 amino-acids) relative to the small range of experimental affinities (2 kcal/mol) and demonstrates good sensitivity of this computational method for simulating peptide fusion inhibitors. Finally, inspection of simulation trajectories identified a highly populated pi-type hydrogen bond, which formed between Gln575 on the receptor and the aromatic ring of peptide ligand Phe631, which could have important implications for drug design.

Comparison of multiple Amber force fields and development of improved protein backbone parameters.

The ff94 force field that is commonly associated with the Amber simulation package is one of the most widely used parameter sets for biomolecular simulation. After a decade of extensive use and testing, limitations in this force field, such as over-stabilization of alpha-helices, were reported by us and other researchers. This led to a number of attempts to improve these parameters, resulting in a variety of "Amber" force fields and significant difficulty in determining which should be used for a particular application. We show that several of these continue to suffer from inadequate balance between different secondary structure elements. In addition, the approach used in most of these studies neglected to account for the existence in Amber of two sets of backbone phi/psi dihedral terms. This led to parameter sets that provide unreasonable conformational preferences for glycine. We report here an effort to improve the phi/psi dihedral terms in the ff99 energy function. Dihedral term parameters are based on fitting the energies of multiple conformations of glycine and alanine tetrapeptides from high level ab initio quantum mechanical calculations. The new parameters for backbone dihedrals replace those in the existing ff99 force field. This parameter set, which we denote ff99SB, achieves a better balance of secondary structure elements as judged by improved distribution of backbone dihedrals for glycine and alanine with respect to PDB survey data. It also accomplishes improved agreement with published experimental data for conformational preferences of short alanine peptides and better accord with experimental NMR relaxation data of test protein systems.

Using PC clusters to evaluate the transferability of molecular mechanics force fields for proteins.

The transferability of molecular mechanics parameters derived for small model systems to larger biopolymers such as proteins can be difficult to assess. Even for small peptides, molecular dynamics simulations are typically too short to sample structures significantly different than initial conformations, making comparison to experimental data questionable. We employed a PC cluster to generate large numbers of native and non-native conformations for peptides with experimentally measured structural data, one predominantly helical and the other forming a beta-hairpin. These atomic-detail sets do not suffer from slow convergence, and can be used to rapidly evaluate important force field properties. In this case a suspected bias toward alpha-helical conformations in the ff94 and ff99 force fields distributed with the AMBER package was verified. The sets provide critical feedback not only on force field transferability, but may also predict modifications for improvement. Such predictions were used to modify the ff99 parameter set, and the resulting force field was used to test stability and folding of model peptides. Structural behavior during molecular dynamics with the modified force field is found to be very similar to expectations, suggesting that these basis sets of conformations may themselves have significant transferability among force fields. We continue to improve and expand this data set and plan to make it publicly accessible. The calculations involved in this process are trivially parallel and can be performed using inexpensive personal computers with commodity components.

All-atom structure prediction and folding simulations of a stable protein.

We present results from all-atom, fully unrestrained ab initio folding simulations for a stable protein with nontrivial secondary structure elements and a hydrophobic core. The construct, "trpcage", is a 20-residue sequence optimized by the Andersen group at University of Washington and is currently the smallest protein that displays two-state folding properties. Compared over the well-defined regions of the experimental structure, our prediction has a remarkably low 0.97 A Calpha root-mean-square-deviation (rmsd) and 1.4 A for all heavy atoms. The simulated structure family displays additional features that are suggested by experimental data, yet are not evident in the family of NMR-derived structures.