Orismilast in moderate-to-severe psoriasis: Efficacy and safety from a 16-week, randomized, double-blinded, placebo-controlled, dose-finding, and phase 2b trial (IASOS).

BACKGROUND: Orismilast is a novel oral phosphodiesterase-4 (PDE4) B/D inhibitor being investigated as a potential treatment for moderate-to-severe psoriasis. OBJECTIVE: To evaluate efficacy and safety of orismilast modified-release formulation in moderate-to-severe psoriasis. METHODS: This multicenter, randomized (1:1:1:1 to 20, 30, 40 mg orismilast or placebo, twice daily), double-blinded, placebo-controlled, parallel-group, phase 2b, 16-week, dose-ranging study evaluated orismilast in adults with moderate-to-severe plaque psoriasis (NCT05190419). Efficacy end points were analyzed using multiple imputation. RESULTS: Of 202 randomized patients, baseline characteristics were balanced across arms, except greater severe disease proportions for orismilast vs placebo. Orismilast showed significant improvements in the primary end point, percentage change in Psoriasis Area and Severity Index (PASI), from baseline to week 16 (orismilast -52.6% to -63.7% and placebo, -17.3%; all P <.001). Greater proportions receiving orismilast achieved PASI75 (39.5%-49.0%; P <.05) and PASI90 (22.0%-28.3%; P <.05 for 20 and 40 mg) vs placebo (PASI75, 16.5% and PASI90, 8.3%) at week 16. Safety findings were as expected with PDE4 inhibition; dose-dependent tolerability effects observed. LIMITATIONS: Small sample size, disease severity imbalance between groups, limited duration and diversity in study population. CONCLUSION: Orismilast demonstrated greater efficacy vs placebo and a safety profile in line with PDE4 inhibition.

Approaches to Synthesis and Isolation of Enantiomerically Pure Biologically Active Atropisomers.

Atropisomerism is a stereochemical phenomenon exhibited by molecules containing a rotationally restricted σ bond. Contrary to classical point chirality, the two atropisomeric stereoisomers exist as a dynamic mixture and can be interconverted without the requirement of breaking and reforming a bond. Although this feature increases structural complexity, atropisomers have become frequent targets in medicinal chemistry projects. Their axial chirality, e.g., from axially chiral biaryl motifs, gives access to unique 3D structures. It is often desirable to have access to both enantiomers of the atropisomers via a nonselective reaction during the early discovery phase as it allows the medicinal chemistry team to probe the structure activity relationship in both directions. However, once a single atropisomer is selected, it presents several problems. First, the pure single atropisomer may interconvert to the undesired stereoisomer under certain conditions. Second, separation of atropisomers is nontrivial and often requires expensive chiral stationary phases using chromatography or additives if a salt resolution approach is chosen. Other options can be kinetic resolution using enzymes or chiral catalysts. However, apart from the high cost often associated with the two latter methods, a maximum yield of only 50% of the desired atropisomer can be obtained. The ideal approach is to install the chiral atropisomeric axis enantioselectively or employing a dynamic kinetic resolution approach. In theory, both approaches have the potential to provide a single atropisomer in quantitative yield. This Account will discuss the successes/failures and challenges we have experienced in developing methods for resolution/separation and asymmetric synthesis of atropisomeric drug candidates in one of our early phase drug development projects. Suitability for the different methods at various stages of the drug development phase is discussed. Depending on the scale and time available, a separation of a mixture of atropisomers by chromatography was sometimes preferred, whereas asymmetric- or resolution approaches were desired for long-term supply. With the use of chromatography, the impact on separation efficiency and solvent consumption, depending on the nature of the substrate, is discussed. We hope that with this Account the readers will get a better view on the challenges medicinal and process chemists meet when designing new atropisomeric drug candidates and developing processes for manufacture of a single atropisomer.

How well does molecular simulation reproduce environment-specific conformations of the intrinsically disordered peptides PLP, TP2 and ONEG?

Understanding the conformational ensembles of intrinsically disordered proteins and peptides (IDPs) in their various biological environments is essential for understanding their mechanisms and functional roles in the proteome, leading to a greater knowledge of, and potential treatments for, a broad range of diseases. To determine whether molecular simulation is able to generate accurate conformational ensembles of IDPs, we explore the structural landscape of the PLP peptide (an intrinsically disordered region of the proteolipid membrane protein) in aqueous and membrane-mimicking solvents, using replica exchange with solute scaling (REST2), and examine the ability of four force fields (ff14SB, ff14IDPSFF, CHARMM36 and CHARMM36m) to reproduce literature circular dichroism (CD) data. Results from variable temperature (VT) 1H and Rotating frame Overhauser Effect SpectroscopY (ROESY) nuclear magnetic resonance (NMR) experiments are also presented and are consistent with the structural observations obtained from the simulations and CD. We also apply the optimum simulation protocol to TP2 and ONEG (a cell-penetrating peptide (CPP) and a negative control peptide, respectively) to gain insight into the structural differences that may account for the observed difference in their membrane-penetrating abilities. Of the tested force fields, we find that CHARMM36 and CHARMM36m are best suited to the study of IDPs, and accurately predict a disordered to helical conformational transition of the PLP peptide accompanying the change from aqueous to membrane-mimicking solvents. We also identify an α-helical structure of TP2 in the membrane-mimicking solvents and provide a discussion of the mechanistic implications of this observation with reference to the previous literature on the peptide. From these results, we recommend the use of CHARMM36m with the REST2 protocol for the study of environment-specific IDP conformations. We believe that the simulation protocol will allow the study of a broad range of IDPs that undergo conformational transitions in different biological environments.

Design and Evaluation of the Initial 50th Percentile Female Prototype Rear Impact Dummy, BioRID P50F - Indications for the Need of an Additional Dummy Size.

The objective of this study was to present the design of a prototype rear impact crash test dummy, representing a 50th percentile female, and compare its performance to volunteer response data. The intention was to develop a first crude prototype as a first step toward a future biofidelic 50th percentile female rear impact dummy. The current rear impact crash test dummy, BioRID II, represents a 50th percentile male, which may limit the assessment and development of whiplash protection systems with regard to female occupants. Introduction of this new dummy size will facilitate evaluation of seat and head restraint (HR) responses in both the average sized female and male in rear impacts. A 50th percentile female rear impact prototype dummy, the BioRID P50F, was developed from modified body segments originating from the BioRID II. The mass and rough dimensions of the BioRID P50F is representative of a 50th percentile female. The prototype dummy was evaluated against low severity rear impact sled tests comprising six female volunteers closely resembling a 50th percentile female with regard to stature and mass. The head/neck response of the BioRID P50F prototype resembled the female volunteer response corridors. The stiffness of the thoracic and lumbar spinal joints remained the same as the average sized male BioRID II, and therefore likely stiffer than joints of an average female. Consequently, the peak rearward angular displacement of the head and T1, and the rearward displacement of the T1, were lesser for the BioRID P50F in comparison to the female volunteers. The biofidelity of the BioRID P50F prototype thus has some limitations. Based on a seat response comparison between the BioRID P50F and the BioRID II, it can be concluded that the male BioRID II is an insufficient representation of the average female in the assessment of the dynamic seat response and effectiveness of whiplash protection systems.

Obstacles and risks in the traffic environment for users of powered wheelchairs in Sweden.

OBJECTIVE: According to the European Union, fatal road accidents involving Vulnerable Road Users (VRUs) are equal in proportion to fatal car road accidents (46%). VRUs include individuals with mobility challenges such as the elderly and Powered Wheelchair (PWC) users. The aim of this interdisciplinary qualitative study was to identify obstacles and risks for PWC users by exploring their behaviour and experiences in traffic environments. METHODS: Videos and in-depth interviews with 13 PWC users aged 20-66 were analysed for this study. The interviews and videos, which include real-life outdoor observations, originate from a qualitative study exploring experiences of PWC use on a daily basis in Sweden. Underlying causal factors to identified risks and obstacles were identified, based on human, vehicle (PWC) and environmental factors in accordance with the Haddon Matrix. RESULTS: The results show significant potential for improvement within all three perspectives of the Haddon Matrix used in the analysis. Participants faced and dealt with various obstacles and risks in order to reach their destination. For example, this includes uneven surfaces, differences in ground levels, steep slopes, as well as interactions with other road users and the influence of weather conditions, resulting in PWC users constantly accommodating and coping with the shortcomings of the vehicle and the environment. CONCLUSIONS: There are still major challenges with regard to preventing obstacles and risks in the traffic environment for PWC users. To discern PWC users in traffic accident and injury data bases, a start would be to register type of aid used for persons involved in an accident. Furthermore, to emphasise PWC users' role as VRUs, it may also be advantageous to describe them as drivers rather than users when navigating the traffic environment. Given the limited sample, further research covering more data from a broader perspective would be beneficial. By incorporating emerging knowledge of PWC users' prerequisites and needs, and including them in research and traffic planning, the society will grow safer and more inclusive, and become better prepared for meeting future demands on accessibility from an aging population.

STEM Tomography of Au Helical Assemblies.

Composite, helical nanostructures formed using cooperative interactions of liquid crystals and Au nanoparticles were studied using a scanning transmission electron microscopy (STEM) mode. The investigated helical assemblies exhibit long-range hierarchical order across length scales, as a result of the crystallization (freezing) directed growth mechanism of nanoparticle-coated twisted nanoribbons and their ability to form organized bundles. Here, STEM methods were used to reproduce the 3D structure of the Au nanoparticle double helix.

Dynamic Responses of Female Volunteers in Rear Impact Sled Tests at Two Head Restraint Distances.

The objective of this study was to assess the biomechanical and kinematic responses of female volunteers with two different head restraint (HR) configurations when exposed to a low-speed rear loading environment. A series of rear impact sled tests comprising eight belted, near 50th percentile female volunteers, seated on a simplified laboratory seat, was performed with a mean sled acceleration of 2.1 g and a velocity change of 6.8 km/h. Each volunteer underwent two tests; the first test configuration, HR10, was performed at the initial HR distance ∼10 cm and the second test configuration, HR15, was performed at ∼15 cm. Time histories, peak values and their timing were derived from accelerometer data and video analysis, and response corridors were also generated. The results were separated into three different categories, HR10 C (N = 8), HR15 C (N = 6), and HR15 N C (N = 2), based on: (1) the targeted initial HR distance [10 cm or 15 cm] and (2) whether the volunteers' head had made contact with the HR [Contact (C) or No Contact (NC)] during the test event. The results in the three categories deviated significantly. The greatest differences were found for the average peak head angular displacements, ranging from 10° to 64°. Furthermore, the average neck injury criteria (NIC) value was 22% lower in HR10 C (3.9 m2/s2), and 49% greater in HR15 N C (7.4 m2/s2) in comparison to HR15 C (5.0 m2/s2). This study supplies new data suitable for validation of mechanical or mathematical models of a 50th percentile female. A model of a 50th percentile female remains to be developed and is urgently required to complement the average male models to enhance equality in safety assessments. Hence, it is important that future protection systems are developed and evaluated with female properties taken into consideration too. It is likely that the HR15 test configuration is close to the limit for avoiding HR contact for this specific seat setup. Using both datasets (HR15 C and HR15 N C ), each with its corresponding HR contact condition, will be possible in future dummy or model evaluation.

Unexpected carbonate salt formation during isolation of an enantiopure intermediate by supercritical fluid chromatography.

The enantiomers of a chiral building block to be used in pre-clinical manufacturing were separated using supercritical fluid chromatography (SFC). Despite an extensive evaluation of different columns and solvent combinations followed by a careful optimization of the chromatographic method, the preparative separation suffered from low throughput and high solvent consumption. Consequently, additional improvements were necessary. By utilizing stacked injections, the chromatographic run time was almost halved, and the high solvent consumption was reduced by recycling of the two mobile phase components, carbon dioxide and methanol. The carbon dioxide was reprocessed by the SFC instrument, whereas methanol was evaporated and recycled from the fractions collected. Hence, the originally inefficient separation method was turned into a more sustainable one, and the desired enantiopure intermediate was delivered to be used in the following synthesis of the selected candidate drug. Unfortunately, when the intermediate was used in the subsequent amide coupling, a surprisingly poor yield was obtained. This was caused by an unexpected formation of a stable carbonate salt of the intermediate under the chromatographic conditions used. By removal of the carbonate prior to the amide coupling reaction, the manufacturing campaign could be saved, and the candidate drug was successfully delivered in time.

Metal-Organic Framework for Transparent Electronics.

Electronics allowing for visible light to pass through are attractive, where a key challenge is to make the core functional units transparent. Here, it is shown that transparent electronics can be constructed by epitaxial growth of metal-organic frameworks (MOFs) on single-layer graphene (SLG) to give a desirable transparency of 95.7% to 550 nm visible light and an electrical conductivity of 4.0 × 104 S m-1. Through lattice and symmetry match, collective alignment of MOF pores and dense packing of MOFs vertically on SLG are achieved, as directly visualized by electron microscopy. These MOF-on-SLG constructs are capable of room-temperature recognition of gas molecules at the ppb level with a linear range from 10 to 108 ppb, providing real-time gas monitoring function in transparent electronics. The corresponding devices can be fabricated on flexible substrates with large size, 3 × 5 cm, and afford continuous folding for more than 200 times without losing conductivity or transparency.

Catalytic Activity of trans-Bis(pyridine)gold Complexes.

Gold catalysis has become one of the fastest growing fields in chemistry, providing new organic transformations and offering excellent chemoselectivities under mild reaction conditions. Methodological developments have been driven by wide applicability in the synthesis of complex structures, whereas the mechanistic understanding of Au(III)-mediated processes remains scanty and have become the Achilles' heel of methodology development. Herein, the systematic investigation of the reactivity of bis(pyridine)-ligated Au(III) complexes is presented, based on NMR spectroscopic, X-ray crystallographic, and DFT data. The electron density of pyridines modulates the catalytic activity of Au(III) complexes in propargyl ester cyclopropanation of styrene. To avoid strain induced by a ligand with a nonoptimal nitrogen-nitrogen distance, bidentate bis(pyridine)-Au(III) complexes convert into dimers. For the first time, bis(pyridine)Au(I) complexes are shown to be catalytically active, with their reactivity being modulated by strain.

Hydrogen Bond Enhanced Halogen Bonds: A Synergistic Interaction in Chemistry and Biochemistry.

The halogen bond (XB) has become an important tool for molecular design in all areas of chemistry, including crystal and materials engineering and medicinal chemistry. Its similarity to the hydrogen bond (HB) makes the relationship between these interactions complex, at times competing against and other times orthogonal to each other. Recently, our two laboratories have independently reported and characterized a synergistic relationship, in which the XB is enhanced through direct intramolecular HBing to the electron-rich belt of the halogen. In one study, intramolecular HBing from an amine polarizes the iodopyridinium XB donors of a bidentate anion receptor. The resulting HB enhanced XB (or HBeXB) preorganizes and further augments the XB donors. Consequently, the affinity of the receptor for halogen anions was significantly increased. In a parallel study, a meta-chlorotyrosine was engineered into T4 lysozyme, resulting in a HBeXB that increased the thermal stability and activity of the enzyme at elevated temperatures. The crystal structure showed that the chlorine of the noncanonical amino acid formed a XB to the protein backbone, which augmented the HB of the wild-type enzyme. Calorimetric analysis resulted in an enthalpic contribution of this Cl-XB to the stability of the protein that was an order of magnitude greater than previously determined in biomolecules. Quantum mechanical (QM) calculations showed that rotating the hydroxyl group of the tyrosine to point toward rather than away from the halogen greatly increased its potential to serve as a XB donor, equivalent to what was observed experimentally. In sum, the two systems described here show that the HBeXB concept extends the range of interaction energies and geometries to be significantly greater than that of the XB alone. Additionally, surveys of structural databases indicate that the components for this interaction are already present in many existing molecular systems. The confluence of the independent studies from our two laboratories demonstrates the reach of the HBeXB across both chemistry and biochemistry and that intentional engineering of this enhanced interaction will extend the applications of XBs beyond these two initial examples.

Acute injuries resulting from accidents involving powered mobility devices (PMDs)-Development and outcomes of PMD-related accidents in Sweden.

Objective: Powered mobility devices (PMDs) are commonly used as aids for older people and people with disabilities, subgroups of vulnarable road users (VRUs) who are rarely noted in traffic safety contexts. However, the problem of accidents involving PMD drivers has been reported in many countries where these vehicles have become increasingly popular. The aim of this study is to extract and analyze national PMD-related accident and injury data reported to the Swedish Traffic Accident Data Acquisition (STRADA) database. The results will provide valuable insight into the risks and obstacles that PMD drivers are exposed to in the traffic environment and may contribute to improving the mobility of this group in the long term. Methods: The current study is based on data from 743 accidents and 998 persons. An analysis was performed on a subset of data (N = 301) in order to investigate the development of accidents over a period of 10 years. Thereafter, each accident in the whole data set was registered as either single (N = 427) or collision (N = 315). Results: The results show that there was a 3-fold increase in the number of PMD-related accidents reported to STRADA during the period 2007-2016. With regard to single accidents, collisions, as well as fatalities, the injury statistics were dominated by males. Single accidents were more common than collisions (N = 427 and N = 316, respectively) and the level of injury sustained in each type of accident is on par. The vast majority of single accidents resulted in the PMD driver impacting the ground (87%), due to either PMD turnover (71%) or the driver falling out of the PMD (16%). The reason for many of the single accidents was a difference in ground level (34%, typically a curb). Cars, trucks, or buses were involved in 67% of collision events; these occured predominantly at junctions or intersections (70%). Abbreviated Injury Scale (AIS) 3+ injuries were dominated by hip and head injuries in both single accidents and collision events. Conclusions: The present study shows that further research on PMD accidents is required, with regard to both single accidents and collision events. To ensure that appropriate decisions are made, future work should follow up on injury trends and further improve the quality of PDM-related accident data. Improved vehicle stability and design, increased usage of safety equipment, proper training programs, effective maintenance services, and development of a supporting infrastructure would contribute to increased safety for PMD drivers.

Carbon's Three-Center, Four-Electron Tetrel Bond, Treated Experimentally.

Tetrel bonding is the noncovalent interaction of group IV elements with electron donors. It is a weak, directional interaction that resembles hydrogen and halogen bonding yet remains barely explored. Herein, we present an experimental investigation of the carbon-centered, three-center, four-electron tetrel bond, [N-C-N]+, formed by capturing a carbenium ion with a bidentate Lewis base. NMR-spectroscopic, titration-calorimetric, and reaction-kinetic evidence for the existence and structure of this species is reported. The studied interaction is by far the strongest tetrel bond reported so far and is discussed in comparison with the analogous halogen bond. The necessity of the involvement of a bidentate Lewis base in its formation is demonstrated by providing spectroscopic and crystallographic evidence that a monodentate Lewis base induces a reaction rather than stabilizing the tetrel bond complex. A vastly decreased Lewis basicity of the bidentate ligand or reduced Lewis acidity of the carbenium ion weakens-or even prohibits-the formation of the tetrel bond complex, whereas synthetic modifications facilitating attractive orbital overlaps promote it. As the geometry of the complex resembles the SN2 transition state, it provides a model system for the investigation of fundamental reaction mechanisms and chemical bonding theories.

Increasing Enzyme Stability and Activity through Hydrogen Bond-Enhanced Halogen Bonds.

The construction of more stable proteins is important in biomolecular engineering, particularly in the design of biologics-based therapeutics. We show here that replacing the tyrosine at position 18 (Y18) of T4 lysozyme with the unnatural amino acid m-chlorotyrosine ( mClY) increases both the thermal stability (increasing the melting temperature by ∼1 °C and the melting enthalpy by 3 kcal/mol) and the enzymatic activity at elevated temperatures (15% higher than that of the parent enzyme at 40 °C) of this classic enzyme. The chlorine of mClY forms a halogen bond (XB) to the carbonyl oxygen of the peptide bond at glycine 28 (G28) in a tight loop near the active site. In this case, the XB potential of the typically weak XB donor Cl is shown from quantum chemical calculations to be significantly enhanced by polarization via an intramolecular hydrogen bond (HB) from the adjacent hydroxyl substituent of the tyrosyl side chain, resulting in a distinctive synergistic HB-enhanced XB (or HeX-B for short) interaction. The larger halogens (bromine and iodine) are not well accommodated within this same loop and, consequently, do not exhibit the effects on protein stability or function associated with the HeX-B interaction. Thus, we have for the first time demonstrated that an XB can be engineered to stabilize and increase the activity of an enzyme, with the increased stabilizing potential of the HeX-B further extending the application of halogenated amino acids in the design of more stable protein therapeutics.

Sex-related illness perception and self-management of a Thai type 2 diabetes population: a cross-sectional descriptive design.

BACKGROUND: Increased knowledge concerning the differences in the illness perception and self-management among sexes is needed for planning proper support programs for patients with diabetes. The aim of this study was to investigate the illness perception and self-management among Thai women and Thai men with type 2 diabetes and to investigate the psychometric properties of the translated instruments used. METHODS: In a suburban province of Thailand, 220 women and men with type 2 diabetes participated in a cross-sectional descriptive study. The participants were selected using a multistage sampling method. Data were collected through structured interviews and were analyzed using group comparisons, and psychometric properties were tested. RESULTS: Women and men with type 2 diabetes demonstrated very similar experiences regarding their illness perception and no differences in self-management. Women perceived more negative consequences of the disease and more fluctuation in the symptoms than men, whereas men felt more confident about the treatment effectiveness than women. Furthermore, the translated instruments used in this study showed acceptable validity and reliability. CONCLUSIONS: The Thai sociocultural context may influence people's perceptions and affect the self-care activities of Thai individuals, both women and men, with type 2 diabetes, causing differences from those found in the Western environment. Intervention programs that aim to improve the effectiveness of the self-management of Thai people with diabetes might consider a holistic and sex-related approach as well as incorporating Buddhist beliefs.

Sex-based differences in pain distribution in a cohort of patients with persistent post-traumatic neck pain.

OBJECTIVES: To analyze a cohort of 745 consecutive patients referred to a regional specialist clinic for evaluation of post-traumatic neck pain during a five-year period. METHODS: A cross-sectional observational study of baseline assessments performed by multi-professional rehabilitation teams according to a standardized checklist. RESULTS: The cohort contained nearly twice as many females as males (64% versus 36%). The type of injury did not differ between sexes. Of the entire cohort, 38% were diagnosed with widespread pain, 50% with regional pain, and 12% with local pain. The pain distribution among the females was 43% widespread, 48% regional, and 9% local, and corresponding figures among males were 29%, 53%, and 18%. Longer time between trauma and assessment did not affect pain distribution among the men, but a tendency towards more widespread pain was observed among the women. DISCUSSION: The importance of "female sex" as risk factor for the development of persistent pain after neck trauma needs to be discussed further. The high frequency of regional and widespread pain among patients with persistent neck pain after trauma calls for both multidisciplinary assessments and treatment strategies. The relationships between different pain distribution patterns, disability, activity, and psychological factors need to be studied further. Implications for rehabilitation Patients suffering from pain and disability after neck trauma constitute a significant proportion of patients with persistent pain. The importance of the risk factor "female sex" should be further discussed in the development of persistent pain after neck trauma. The high frequency of regional and widespread pain among patients with persistent neck pain after trauma calls both for multidisciplinary assessments and treatment strategies. The relationships between different pain distribution patterns, disability, activity, and psychological factors need to be studied further.

Structure-Energy Relationships of Halogen Bonds in Proteins.

The structures and stabilities of proteins are defined by a series of weak noncovalent electrostatic, van der Waals, and hydrogen bond (HB) interactions. In this study, we have designed and engineered halogen bonds (XBs) site-specifically to study their structure-energy relationship in a model protein, T4 lysozyme. The evidence for XBs is the displacement of the aromatic side chain toward an oxygen acceptor, at distances that are equal to or less than the sums of their respective van der Waals radii, when the hydroxyl substituent of the wild-type tyrosine is replaced by a halogen. In addition, thermal melting studies show that the iodine XB rescues the stabilization energy from an otherwise destabilizing substitution (at an equivalent noninteracting site), indicating that the interaction is also present in solution. Quantum chemical calculations show that the XB complements an HB at this site and that solvent structure must also be considered in trying to design molecular interactions such as XBs into biological systems. A bromine substitution also shows displacement of the side chain, but the distances and geometries do not indicate formation of an XB. Thus, we have dissected the contributions from various noncovalent interactions of halogens introduced into proteins, to drive the application of XBs, particularly in biomolecular design.

Real-world adjustments of driver seat and head restraint in Saab 9-3 vehicles.

OBJECTIVE: Whiplash-associated disorder (WAD), commonly denoted whiplash injury, is a worldwide problem. These injuries occur at relatively low changes of velocity (typically <25 km/h) in impacts from all directions. Rear impacts, however, are the most common in the injury statistics. Females have a 1.5-3 times higher risk of whiplash injury than males. Improved seat design is the prevailing means of increasing the protection of whiplash injury for occupants in rear impacts. Since 1997, more advanced whiplash protection systems have been introduced on the market, the Saab Active Head Restraint (SAHR) being one of the most prominent. The SAHR-which is height adjustable-is mounted to a pressure plate in the seatback by means of a spring-resisted link mechanism. Nevertheless, studies have shown that seats equipped with reactive head restraints (such as the SAHR) have a very high injury-reducing effect for males (∼60-70%) but very low or no reduction effect for females. One influencing factor could be the position of the head restraint relative to the head, because a number of studies have reported that adjustable head restraints often are incorrectly positioned by drivers. The aim was to investigate how female and male Saab drivers adjust the seat in the car they drive the most. METHODS: The seated positions of drivers in stationary conditions have been investigated in a total of 76 volunteers (34 females, 42 males) who participated in the study. Inclusion criteria incorporated driving a Saab 9-3 on a regularly basis. RESULTS: The majority of the volunteers (89%) adjusted the head restraint to any of the 3 uppermost positions and as many as 59% in the top position. The average vertical distance between the top of the head and the top of the head restraint (offset) increase linearly with increasing statures, from an average of -26 mm (head below the head restraint) for small females to an average of 82 mm (head above the head restraint) for large males. On average, the offset was 23 mm for females, which is within a satisfactory range and in accordance with recommendations; the corresponding value for males was 72 mm. The backset tended to be shorter among female volunteers (on average 27 mm) compared to the male volunteers (on average 44 mm). Moreover, the backset tended to increase with increasing statures. CONCLUSIONS: Incorrect adjustment of the head restraint cannot explain the large differences found between the sexes in the effectiveness of the SAHR system.

Substituent Effects on the [N-I-N](+) Halogen Bond.

We have investigated the influence of electron density on the three-center [N-I-N](+) halogen bond. A series of [bis(pyridine)iodine](+) and [1,2-bis((pyridine-2-ylethynyl)benzene)iodine](+) BF4(-) complexes substituted with electron withdrawing and donating functionalities in the para-position of their pyridine nitrogen were synthesized and studied by spectroscopic and computational methods. The systematic change of electron density of the pyridine nitrogens upon alteration of the para-substituent (NO2, CF3, H, F, Me, OMe, NMe2) was confirmed by (15)N NMR and by computation of the natural atomic population and the π electron population of the nitrogen atoms. Formation of the [N-I-N](+) halogen bond resulted in >100 ppm (15)N NMR coordination shifts. Substituent effects on the (15)N NMR chemical shift are governed by the π population rather than the total electron population at the nitrogens. Isotopic perturbation of equilibrium NMR studies along with computation on the DFT level indicate that all studied systems possess static, symmetric [N-I-N](+) halogen bonds, independent of their electron density. This was further confirmed by single crystal X-ray diffraction data of 4-substituted [bis(pyridine)iodine](+) complexes. An increased electron density of the halogen bond acceptor stabilizes the [N···I···N](+) bond, whereas electron deficiency reduces the stability of the complexes, as demonstrated by UV-kinetics and computation. In contrast, the N-I bond length is virtually unaffected by changes of the electron density. The understanding of electronic effects on the [N-X-N](+) halogen bond is expected to provide a useful handle for the modulation of the reactivity of [bis(pyridine)halogen](+)-type synthetic reagents.