Is the relationship between chronic pain and mortality causal? A propensity score analysis.

ABSTRACT: Chronic pain is a serious and prevalent condition that can affect many facets of life. However, uncertainty remains regarding the strength of the association between chronic pain and death and whether the association is causal. We investigate the pain-mortality relationship using data from 19,971 participants aged 51+ years in the 1998 wave of the U.S. Health and Retirement Study. Propensity score matching and inverse probability weighting are combined with Cox proportional hazards models to investigate whether exposure to chronic pain (moderate or severe) has a causal effect on mortality over a 20-year follow-up period. Hazard ratios (HRs) with 95% confidence intervals (CIs) are reported. Before adjusting for confounding, we find a strong association between chronic pain and mortality (HR: 1.32, 95% CI: 1.26-1.38). After adjusting for confounding by sociodemographic and health variables using a range of propensity score methods, the estimated increase in mortality hazard caused by pain is more modest (5%-9%) and the results are often also compatible with no causal effect (95% CIs for HRs narrowly contain 1.0). This attenuation highlights the role of confounders of the pain-mortality relationship as potentially modifiable upstream risk factors for mortality. Posing the depressive symptoms variable as a mediator rather than a confounder of the pain-mortality relationship resulted in stronger evidence of a modest causal effect of pain on mortality (eg, HR: 1.08, 95% CI: 1.01-1.15). Future work is required to model exposure-confounder feedback loops and investigate the potentially cumulative causal effect of chronic pain at multiple time points on mortality.

In vivo measurement of strain in the periodontal space of pig (Sus scrofa) incisors using in-fiber Bragg sensors.

The incisor teeth in pigs, Sus scrofa, function in association with a disc-shaped snout to explore the environment for potential food. Understanding how mechanical loading applied to the tooth deforms the periodontal ligament (PDL) is important to determining the role of periodontal mechanoreceptors during food exploration and feeding. The objective of this study was to use fiber Bragg (FBG) sensors to measure strain in vivo within the PDL space of pig incisors. The central mandibular incisors of pigs underwent spring loaded lingual tipping during FBG strain recording within the labial periodontal space. FBG sensors were placed within the periodontal space of the central mandibular incisors of ~2-3-month-old farm pigs. The magnitude and orientation of spring loads are expected to mimic incisor contact with food. During incisor tipping with load calibrated springs, FBG strains in vitro (N = 6) and in vivo (N = 6) recorded at comparable load levels overlapped in range (-10-20 µÎµ). Linear regressions between peak FBG strains, that is, the highest recorded strain value, and baseline strains, that is, strain without applied spring load, were significant across all in vivo experiments (peak strain at 200 g vs. baseline, p = .04; peak strain at 2000 g vs. baseline p = .03; peak strain at 2000 g vs. 200 g, p = .004). These linear relationships indicate that on a per experiment basis, the maximum measured strain at different spring loads showed predictable differences. A Friedman test of the absolute value of peak strain confirmed the significant increase in strain between baseline, 200 g, and 2000 g spring activation (p = .02). Mainly compressive strains were recorded in the labial PDL space and increases in spring load applied in vivo generated increases in FBG strain measurements. These results demonstrate the capacity for FBG sensors to be used in vivo to assess transmission of occlusal loads through the periodontium. PDL strain is associated with mechanoreceptor stimulation and is expected to affect the functional morphology of the incisors. The overall low levels of strain observed may correspond with the robust functional morphology of pig incisors and the tendency for pigs to encounter diverse foods and substrates during food exploration.

A Preliminary Step Towards a Physical Surrogate of the Human Calvarium to Model Fracture.

A surrogate model of the human calvarium can be used to assess skull-fracture-related head injuries without continuously requiring post-mortem human skulls. Skull simulants developed in the literature often require sophisticated manufacturing procedures and/or materials not always practical when factoring in time or expense considerations. This study's objective was to fabricate three exploratory surrogate models (1. pure epoxy prototype, 2. epoxy-chalk mix prototype, and 3. epoxy-chalk three-layered prototype) of the calvarium to mimic the calvarium's mechanical response at fracture using readily available and cost-effective materials, specifically epoxy and chalk. The surrogates and calvaria were subject to quasi-static and dynamic impact 4-point bending and their mechanical responses were compared statistically. Under quasi-static loading, all three surrogates showed a considerable number of differences in mechanical response variables to calvaria that was deemed significant (p < 0.05). Under dynamic impact loading, there was no sufficient evidence to reject that the average mechanical response variables were equal between the epoxy-chalk three-layered prototype and calvaria (p > 0.05). This included force and bending moment at fracture, tensile strain at fracture, tensile and compressive stress at fracture, tensile modulus, and tensile strain rate. Overall, our study illustrates two main remarks: (1) the three exploratory surrogate models are potential candidates for mimicking the mechanical response of the calvarium at fracture during impact loading and (2) employing epoxy and chalk, which are readily available and cost-effective has the potential to mimic the mechanical response of calvaria in impact loading.

In-fiber Bragg sensor measurements assess fluid effects on strain in the periodontal space of an ex-vivo swine incisor complex under mechanical loading.

The purpose of this study is to determine whether in-fiber Bragg grating (FBG) sensors detect changes within the periodontal ligament (PDL) of ex-vivo swine tooth-PDL-bone complex (TPBC) when manipulating fluid content. Recording strain will allow for a better understanding of the biomechanics of viscoelastic load transfer from the tooth to the PDL during chewing and/or orthodontic tooth movement, as well as replication of these dynamics in regenerated PDL tissues. FBG sensors placed within the PDL of swine incisor teeth were used to measure strain resulting from an intrusive load. Specimens were mounted in a custom platform within an MTS machine and a compressive load was applied at 0.3 mm/s to a depth of 0.5 mm and held for 10 s. Median peak strain and load and median absolute deviation (MAD) were compared: dry vs. saline (n = 19) with bias-corrected bootstrap 95% CI. Dry vs. saline conditions did not statistically differ (median peaks of 5µÎµ, 103-105 N) and recorded strains showed high repeatability (MAD of 0.82µÎµ, 0.72µÎµ, respectively). FBG sensors did not detect the fluid changes in this study, suggesting that the deformation of tissues in the PDL space collectively determine FBG strain in response to tooth loading. The repeatability of measurements demonstrates the potential for FBG sensors to assess the strain in the PDL space of an in vivo swine model.

The effect of morphometric and geometric indices of the human calvarium on mechanical response.

BACKGROUND: When developing a surrogate model of the human skull, there is a multitude of morphometric and geometric properties to consider when constructing the model. To simplify this approach, it is important to identify only the properties that have a significant influence on the mechanical response of the skull. The objective of this study was to identify which morphometric and geometric properties of the calvarium were significant predictors of mechanical response. METHODS: Calvarium specimens (N = 24) were micro-computed tomography scanned to determine morphometric and geometric properties. The specimens were assumed to be Euler-Bernoulli beams and were subject to 4-point quasi-static bending to determine mechanical response. Univariate linear regressions were performed whereby the morphometric and geometric properties were independent or predictor variables and the mechanical responses were dependent or outcome variables. FINDINGS: Nine significant linear regression models were established (p < 0.05). In the diploë, trabecular bone pattern factor was a significant predictor of force and bending moment at fracture. The inner cortical table had more significant predictors (thickness, tissue mineral density, and porosity) of mechanical response compared to the outer cortical table and diploë. INTERPRETATION: Morphometric and geometric properties had a key influence on the calvarium's biomechanics. Trabecular bone pattern factor and the morphometry and geometry of the cortical tables must be considered when evaluating the mechanical response of the calvarium. These properties can aid the design of surrogate models of the skull that seek to mimic its mechanical response for head impact simulation.

Important Structural Features of Thiolate-Rich Four-Helix Bundles for Cu(I) Uptake and Removal.

A family of bacterial copper storage proteins (the Csps) possess thiolate-lined four-helix bundles whose cores can be filled with Cu(I) ions. The majority of Csps are cytosolic (Csp3s), and in vitro studies carried out to date indicate that the Csp3s from Methylosinus trichosporium OB3b (MtCsp3), Bacillus subtilis (BsCsp3), and Streptomyces lividans (SlCsp3) are alike. Bioinformatics have highlighted homologues with potentially different Cu(I)-binding properties from these characterized "classical" Csp3s. Determination herein of the crystal structure of the protein (RkCsp3) from the methanotroph Methylocystis sp. strain Rockwell with Cu(I) bound identifies this as the first studied example of a new subgroup of Csp3s. The most significant structural difference from classical Csp3s is the presence of only two Cu(I) sites at the mouth of the bundle via which Cu(I) ions enter and leave. This is due to the absence of three Cys residues and a His-containing motif, which allow classical Csp3s to bind five to six Cu(I) ions in this region. Regardless, RkCsp3 exhibits rapid Cu(I) binding and the fastest measured Cu(I) removal rate for a Csp3 when using high-affinity ligands as surrogate partners. New experiments on classical Csp3s demonstrate that their His-containing motif is not essential for fast Cu(I) uptake and removal. Other structural features that could be important for these functionally relevant in vitro properties are discussed.

Evaluating the Intracranial Pressure Biofidelity and Response Repeatability of a Physical Head-Brain Model in Frontal Impacts.

Headforms are widely used in head injury research and headgear assessment. Common headforms are limited to replicating global head kinematics, although intracranial responses are crucial to understanding brain injuries. This study aimed to evaluate the biofidelity of intracranial pressure (ICP) and the repeatability of head kinematics and ICP of an advanced headform subjected to frontal impacts. Pendulum impacts were performed on the headform using various impact velocities (1-5 m/s) and impactor surfaces (vinyl nitrile 600 foam, PCM746 urethane, and steel) to simulate a previous cadaveric experiment. Head linear accelerations and angular rates in three axes, cerebrospinal fluid ICP (CSFP), and intraparenchymal ICP (IPP) at the front, side, and back of the head were measured. The head kinematics, CSFP, and IPP demonstrated acceptable repeatability with coefficients of variation generally being less than 10%. The BIPED front CSFP peaks and back negative peaks were within the range of the scaled cadaver data (between the minimum and maximum values reported by Nahum et al.), while side CSFPs were 30.9-92.1% greater than the cadaver data. CORrelation and Analysis (CORA) ratings evaluating the closeness of two time histories demonstrated good biofidelity of the front CSFP (0.68-0.72), while the ratings for the side (0.44-0.70) and back CSFP (0.27-0.66) showed a large variation. The BIPED CSFP at each side was linearly related to head linear accelerations with coefficients of determination greater than 0.96. The slopes for the BIPED front and back CSFP-acceleration linear trendlines were not significantly different from cadaver data, whereas the slope for the side CSFP was significantly greater than cadaver data. This study informs future applications and improvements of a novel head surrogate.

Influence of surrogate scalp material and thickness on head impact responses: Toward a biofidelic head-brain physical model.

Advanced physical head models capable of replicating both global kinematics and intracranial mechanics of the human head are required for head injury research and safety gear assessment. These head surrogates require a complex design to accommodate realistic anatomical details. The scalp is a crucial head component, but its influence on the biomechanical response of such head surrogates remains unclear. This study aimed to evaluate the influence of surrogate scalp material and thickness on head accelerations and intraparenchymal pressures using an advanced physical head-brain model. Scalp pads made from four materials (Vytaflex20, Vytaflex40, Vytaflex50, PMC746) and each material with four thicknesses (2, 4, 6, and 8 mm) were evaluated. The head model attached to the scalp pad was dropped onto a rigid plate from two heights (5 and 19.5 cm) and at three head locations (front, right side, and back). While the selected materials' modulus exhibited a relatively minor effect on head accelerations and coup pressures, the effect of scalp thickness was shown to be major. Moreover, by decreasing the thickness of the head's original scalp by 2 mm and changing the original scalp material from Vytaflex 20 to Vytaflex 40 or Vytaflex 50, the head acceleration biofidelity ratings could improve by 30% and approached the considered rating (0.7) of good biofidelity. This study provides a potential direction for improving the biofidelity of a novel head model that might be a useful tool in head injury research and safety gear tests. This study also has implications for selecting appropriate surrogate scalps in the future design of physical and numerical head models.

The Mechanical Characterization and Comparions of Male and Female Calvaria Under Four-Point Bending Impacts.

The circumstances in which we mechanically test and critically assess human calvarium tissue would find relevance under conditions encompassing real-world head impacts. These conditions include, among other variables, impact velocities, and strain rates. Compared to quasi-static loading on calvaria, there is less reporting on the impact loading of the calvaria and consequently, there are relatively fewer mechanical properties on calvaria at relevant impact loading rates available in the literature. The purpose of this work was to report on the mechanical response of 23 human calvarium specimens subjected to dynamic four-point bending impacts. Impacts were performed using a custom-built four-point impact apparatus at impact velocities of 0.86-0.89 m/s resulting in surface strain rates of 2-3/s-representative of strain rates observed in vehicle collisions and blunt impacts. The study revealed comparable effective bending moduli (11-15 GPa) to the limited work reported on the impact mechanics of calvaria in the literature, however, fracture bending stress (10-47 MPa) was relatively less. As expected, surface strains at fracture (0.21-0.25%) were less compared to studies that performed quasi-static bending. Moreover, the study revealed no significant differences in mechanical response between male and female calvaria. The findings presented in this work are relevant to many areas including validating surrogate skull fracture models in silico or laboratory during impact and optimizing protective devices used by civilians to reduce the risk of a serious head injury.

Review of Mechanisms and Research Methods for Blunt Ballistic Head Injury.

Head injuries account for 15%-20% of all military injuries and pose a high risk of causing functional disability and fatality. Blunt ballistic impacts are one of the threats that can lead to severe head injuries. This review aims to examine the mechanisms and injury risk assessment associated with blunt ballistic head injury (BBHI). The review further discusses research methods and instrumentation used in BBHI studies, focusing on their limitations and challenges. Studies on the mechanisms of focal and diffuse brain injuries remain largely inconclusive and require further effort. Some studies have attempted to associate BBHIs with head mechanics, but more research is required to establish correlations between head mechanics and injury severity. Limited access to experimental models and a lack of instrumentation capable of measuring the mechanics of brain tissue in situ are potential reasons for the lack of understanding of injury mechanisms, injury correlations, and injury tolerance levels specific to this loading regime. Targeted research for understanding and assessing head injuries in blunt ballistic impacts is a necessary step in improving our ability to design protection systems to mitigate these injuries.

Copper delivery to an endospore coat protein of Bacillus subtilis.

A family of cytosolic copper (Cu) storage proteins (the Csps) bind large quantities of Cu(I) via their Cys-lined four-helix bundles, and the majority are cytosolic (Csp3s). The presence of Csp3s in many bacteria appears inconsistent with the current dogma that bacteria, unlike eukaryotes, have evolved not to maintain intracellular pools of Cu due to its potential toxicity. Sporulation in Bacillus subtilis has been used to investigate if a Csp3 binds Cu(I) in the cytosol for a target enzyme. The activity of the Cu-requiring endospore multi-Cu oxidase BsCotA (a laccase) increases under Cu-replete conditions in wild type B. subtilis. In the strain lacking BsCsp3 lower BsCotA activity is observed and is unaffected by Cu levels. BsCsp3 loaded with Cu(I) readily activates apo-BsCotA in vitro. Experiments with a high affinity Cu(I) chelator demonstrate that Cu(I) transfer from Cu(I)-BsCsp3 must occur via an associative mechanism. BsCsp3 and BsCotA are both upregulated during late sporulation. We hypothesise that BsCsp3 acquires cuprous ions in the cytosol of B. subtilis for BsCotA.

Adult Children's Educational Attainment and Parent Health in Mid- and Later-Life.

OBJECTIVES: Intergenerational models of adult health contend that children's educational attainments influence the health and well-being of their parents. However, it is unclear how much of this association is confounded by background characteristics that predict both children's educational attainments and parents' subsequent health, particularly in the United States. METHODS: Data from the National Longitudinal Study of Adolescent to Adult Health Parent Study are used to examine how having no children who completed college influences parents' self-rated health and depressive symptoms. We rely on propensity score methods to more squarely assess this relationship net of potential confounding bias and to test for heterogeneity in the consequences associated with having no children who completed college. RESULTS: Having no children who completed college is negatively associated with parents' self-rated health and positively associated with depressive symptoms. After statistically balancing differences in background characteristics between groups, these associations remain, though the magnitude of the coefficients is attenuated. Supplemental matching analyses suggest that while the association between children's education and self-rated health might be spurious, the association with depressive symptoms is more robust. Additionally, among parents with the highest propensity for having no children who complete college, the consequences on depressive symptoms are greatest. DISCUSSION: This study pays particular attention to selection-related concerns surrounding the association between offspring educational attainment and parent well-being in the United States. These findings are important given the call for investments in children's educational opportunities as promoting both the well-being of adult children and their parents.

Experimental repeatability, sensitivity, and reproducibility of force and strain measurements from within the periodontal ligament space during ex vivo swine tooth loading.

The Periodontal Ligament (PDL) is a complex connective tissue that anchors a tooth to the surrounding alveolar bone. The small size and complex geometry of the PDL space within an intact tooth-PDL-bone complex (TPBC) limits strain measurements. An in-fiber Bragg grating (FBG) sensor offers potential for such measurements due to its small size. This work defines an experimental procedure where strain and force were measured during quasi-static, apically directed, displacement-controlled tests on swine premolar crowns. Specifically, the: inter-TPBC, intra-TPBC, and long-term repeatability after a preconditioned state was objectively identified; sensitivity to preload magnitude, TPBC alignment, and sensor depth; and reproducibility within a TPBC was determined. Data clustering was used to determine the appropriate number of preconditioning trials, ranging from one to seven. Strain and force measurements showed intra-TPBC repeatability with average adjusted root mean square from the median of 28.9% of the peak strain and 4.5% of the peak force measurement. A Mann-Whitney U test generally found statistically significant differences in peak strain and force measurements between the left and right sides, suggesting a lack of inter-TPBC repeatability. Using a Friedman test, it was shown that peak strain measures were sensitive to the TPBC alignment and sensor depth, while peak force measures were sensitive to the preload and TPBC alignment. A Friedman test suggested reproducible strain and force measurements when the FBG was replaced within the same TPBC and the preload, alignment, and sensor depth were controlled.

Repeatability and Biofidelity of a Physical Surrogate Neck Model Fit to a Hybrid III Head.

In helmet impact testing, parameters including acceleration and velocity are measured using instrumented head-neck models that are meant to be mechanically realistic (i.e. biofidelic) stand-ins, or surrogates, for humans. Currently available models of the human neck are designed primarily for application in automotive crash testing, and their applicability in assessment of helmets is often questioned. The object of the present work is to document the mechanical design, repeatability, and biofidelity in low speed impact of a new neck model that we apply with a Hybrid III head. Focusing on Hybrid III head kinematics measured during impacts at 2 to 6 m/s, the co-efficient of variance of repeated measures of kinematics was generally less than 10%. Differences in kinematics between identical copies of the neck was less than 20% when tested with helmets, and less than 7% when the head was not helmeted. In parallel testing using a Hybrid III head-neck, the co-efficient of variance in repeated measures was less than 4% and the kinematics significantly differed from those measured using the new neck. CORAplus scores for the new neck were approximately 0.70 when compared against data for human subjects with passive neck muscles experiencing impact at 2 m/s.

Evaluation of the Kinematic Biofidelity and Inter-Test Repeatability of Global Accelerations and Brain Parenchyma Pressure for a Head-Brain Physical Model.

Head surrogates are widely used in biomechanical research and headgear assessment. They are designed to approximate the inertial and mechanical properties of the head and are instrumented to measure global head kinematics. Due to the recent interest in studying disruption to the brain, some head models include internal fluid layers and brain tissue, and instrumentation to measure head intracranial biomechanics. However, it is unknown whether such models exhibit realistic human responses. Therefore, this study aims to assess the biofidelity and repeatability of a head model, the Blast Injury Protection Evaluation Device (BIPED), that can measure both global head kinematics and intraparenchymal pressure (IPP) for application in blunt impact, a common loading scenario in civilian life. Drop tests were conducted with the BIPED and the widely used Hybrid III headform. BIPED measures were compared to the Hybrid III data and published cadaveric data, and the biofidelity level of the global linear acceleration was quantified using CORrelation and Analysis (CORA) ratings. The repeatability of the acceleration and IPP measurements in multiple impact scenarios was evaluated via the coefficient of variation (COV) of the magnitudes and pulse durations. BIPED acceleration peaks were generally not significantly different from cadaver and Hybrid III data. The CORA ratings for the BIPED and Hybrid III accelerations ranged from 0.50 to 0.61 and 0.51 to 0.77, respectively. The COVs of acceleration and IPP were generally below 10%. This study is an important step toward a biofidelic head surrogate measuring both global kinematics and IPP in blunt impact.

Cortical and trabecular morphometric properties of the human calvarium.

There is currently a gap in the literature that quantitatively describes the complex bone microarchitecture within the diploë (trabecular bone) and cortical layers of the human calvarium. The purpose of this study was to determine the morphometric properties of the diploë and cortical tables of the human calvarium in which key interacting factors of sex, location on the calvarium, and layers of the sandwich structure were considered. Micro-computed tomography (micro-CT) was utilized to capture images at 18 µm resolution of male (n = 26) and female (n = 24) embalmed calvarium specimens in the frontal and parietal regions (N = 50). All images were post-processed and analyzed using vendor bundled CT-Analyzer software to determine the morphometric properties of the diploë and cortical layers. A two-way mixed (repeated measures) analysis of variance (ANOVA) was used to determine diploë morphometric properties accounting for factors of sex and location. A three-way mixed ANOVA was performed to determine cortical morphometric properties accounting for factors of cortical layer (inner and outer table), sex, and location. The study revealed no two-way interaction effects between sex and location on the diploë morphometry except for fractal dimension. Trabecular thickness and separation in the diploë were significantly greater in the male specimens; however, females showed a greater number of trabeculae and fractal dimension on average. Parietal specimens revealed a greater porosity, trabecular separation, and deviation from an ideal plate structure, but a lesser number of trabeculae and connectivity compared to the frontal location. Additionally, the study observed a lower density and greater porosity in the inner cortical layer than the outer which may be due to clear distinctions between each layer's physiological environment. The study provides valuable insight into the quantitative morphometry of the calvarium in which finite element modelers of the skull can refer to when designing detailed heterogenous or subject-specific skull models to effectively predict injury. Furthermore, this study contributes towards the recent developments on physical surrogate models of the skull which require approximate measures of calvarium bone architecture in order to effectively fabricate a model and then accurately simulate a traumatic head impact event.

On the ability of experimental impact measures to predict tooth injuries in an ex vivo swine model.

BACKGROUND/AIM: Impact to the orofacial region, in particular teeth, is a frequent incident leading to injury in many sports and can result in health and economic costs for the injured individual. The majority of previous work has applied synthetic models such as plaster or stone, to form analogs of relevant structures to study the potential for impact-induced injury. Biomechanical studies that have applied tissue models (animal or human) for the purpose of determining the biomechanical measures associated with dental injury are rare. The aim of this study was to apply a simple ex vivo model based on swine dentition to ascertain which of a select list of measurable quantities associated with impact mechanics could predict luxation and fracture of teeth due to impact. METHODS: Mandibular central incisors of ex vivo swine dentitions were impacted using a linear drop tower with heights ranging from 1.20 m to 2.42 m. Seven mechanical predictors were assessed at impact and were then subjected to binary logistic regression techniques to determine which was the best predictor of luxations or fractures of the teeth. RESULTS: Of the seven mechanical predictors, (1) the velocity of the impacting body (R2  = 0.477), (2) a proxy measure for the change in kinetic energy of the impacting body (R2  = 0.586), and (3) the approximate energy absorbed by the tissue (R2  = 0.722) were found to be statistically significantly different (p < .05), offering the greatest specificity as indicated by receiver operator characteristics. Other measures that are frequently used in impact mechanics, including peak linear acceleration and velocity change, were not statistically significant predictors of tooth injury. CONCLUSION: Identifying mechanical predictors for dental injury of unprotected teeth provides a first step in understanding which aspects of an impact event attribute to dental injury and can lay the foundation for future studies that examine alteration in injury mechanics associated with protection devices.