Showing papers by "Dartmouth College published in 2022"

Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain

Abstract:

Importance

Chronic back pain (CBP) is a leading cause of disability, and treatment is often ineffective. Approximately 85% of cases are primary CBP, for which peripheral etiology cannot be identified, and maintenance factors include fear, avoidance, and beliefs that pain indicates injury.

Objective

To test whether a psychological treatment (pain reprocessing therapy [PRT]) aiming to shift patients’ beliefs about the causes and threat value of pain provides substantial and durable pain relief from primary CBP and to investigate treatment mechanisms.

Design, Setting, and Participants

This randomized clinical trial with longitudinal functional magnetic resonance imaging (fMRI) and 1-year follow-up assessment was conducted in a university research setting from November 2017 to August 2018, with 1-year follow-up completed by November 2019. Clinical and fMRI data were analyzed from January 2019 to August 2020. The study compared PRT with an open-label placebo treatment and with usual care in a community sample.

Interventions

Participants randomized to PRT participated in 1 telehealth session with a physician and 8 psychological treatment sessions over 4 weeks. Treatment aimed to help patients reconceptualize their pain as due to nondangerous brain activity rather than peripheral tissue injury, using a combination of cognitive, somatic, and exposure-based techniques. Participants randomized to placebo received an open-label subcutaneous saline injection in the back; participants randomized to usual care continued their routine, ongoing care.

Main Outcomes and Measures

One-week mean back pain intensity score (0 to 10) at posttreatment, pain beliefs, and fMRI measures of evoked pain and resting connectivity.

Results

At baseline, 151 adults (54% female; mean [SD] age, 41.1 [15.6] years) reported mean (SD) pain of low to moderate severity (mean [SD] pain intensity, 4.10 [1.26] of 10; mean [SD] disability, 23.34 [10.12] of 100) and mean (SD) pain duration of 10.0 (8.9) years. Large group differences in pain were observed at posttreatment, with a mean (SD) pain score of 1.18 (1.24) in the PRT group, 2.84 (1.64) in the placebo group, and 3.13 (1.45) in the usual care group. Hedgesgwas −1.14 for PRT vs placebo and −1.74 for PRT vs usual care (P < .001). Of 151 total participants, 33 of 50 participants (66%) randomized to PRT were pain-free or nearly pain-free at posttreatment (reporting a pain intensity score of 0 or 1 of 10), compared with 10 of 51 participants (20%) randomized to placebo and 5 of 50 participants (10%) randomized to usual care. Treatment effects were maintained at 1-year follow-up, with a mean (SD) pain score of 1.51 (1.59) in the PRT group, 2.79 (1.78) in the placebo group, and 3.00 (1.77) in the usual care group. Hedgesgwas −0.70 for PRT vs placebo (P = .001) and −1.05 for PRT vs usual care (P < .001) at 1-year follow-up. Longitudinal fMRI showed (1) reduced responses to evoked back pain in the anterior midcingulate and the anterior prefrontal cortex for PRT vs placebo; (2) reduced responses in the anterior insula for PRT vs usual care; (3) increased resting connectivity from the anterior prefrontal cortex and the anterior insula to the primary somatosensory cortex for PRT vs both control groups; and (4) increased connectivity from the anterior midcingulate to the precuneus for PRT vs usual care.

Conclusions and Relevance

Psychological treatment centered on changing patients’ beliefs about the causes and threat value of pain may provide substantial and durable pain relief for people with CBP.

Trial Registration

ClinicalTrials.gov Identifier:NCT03294148.

Phenotypic heterogeneity driven by plasticity of the intermediate EMT state governs disease progression and metastasis in breast cancer

Abstract: The epithelial-to-mesenchymal transition (EMT) is frequently co-opted by cancer cells to enhance migratory and invasive cell traits. It is a key contributor to heterogeneity, chemoresistance, and metastasis in many carcinoma types, where the intermediate EMT state plays a critical tumor-initiating role. We isolate multiple distinct single-cell clones from the SUM149PT human breast cell line spanning the EMT spectrum having diverse migratory, tumor-initiating, and metastatic qualities, including three unique intermediates. Using a multiomics approach, we identify CBFβ as a key regulator of metastatic ability in the intermediate state. To quantify epithelial-mesenchymal heterogeneity within tumors, we develop an advanced multiplexed immunostaining approach using SUM149-derived orthotopic tumors and find that the EMT state and epithelial-mesenchymal heterogeneity are predictive of overall survival in a cohort of stage III breast cancer. Our model reveals previously unidentified insights into the complex EMT spectrum and its regulatory networks, as well as the contributions of epithelial-mesenchymal plasticity (EMP) in tumor heterogeneity in breast cancer.

Factor Momentum and the Momentum Factor

Abstract: Momentum in individual stock returns relates to momentum in factor returns. Most factors are positively autocorrelated: the average factor earns a monthly return of six basis points following a year of losses and 51 basis points following a positive year. We find that factor momentum concentrates in factors that explain more of the cross section of returns and that it is not incidental to individual stock momentum: momentum-neutral factors display more momentum. Momentum found in high-eigenvalue principal component factors subsumes most forms of individual stock momentum. Our results suggest that momentum is not a distinct risk factor—it times other factors.

Modulation of the Human Pancreatic Ductal Adenocarcinoma Immune Microenvironment by Stereotactic Body Radiotherapy

Abstract: Stereotactic body radiotherapy (SBRT) is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC), which can effectively prime cytotoxic T cells by inducing immunogenic tumor cell death in preclinical models. SBRT effects on human PDAC have yet to be thoroughly investigated; therefore, this study aimed to characterize immunomodulation in the human PDAC tumor microenvironment following therapy.Tumor samples were obtained from patients with resectable PDAC. Radiotherapy was delivered a median of 7 days prior to surgical resection, and sections were analyzed by multiplex IHC (mIHC), RNA sequencing, and T-cell receptor sequencing (TCR-seq).Analysis of SBRT-treated tumor tissue indicated reduced tumor cell density and increased immunogenic cell death relative to untreated controls. Radiotherapy promoted collagen deposition; however, vasculature was unaffected and spatial analyses lacked evidence of T-cell sequestration. Conversely, SBRT resulted in fewer tertiary lymphoid structures and failed to lessen or reprogram abundant immune suppressor populations. Higher percentages of PD-1+ T cells were observed following SBRT, and a subset of tumors displayed more clonal T-cell repertoires.These findings suggest that SBRT augmentation of antitumor immunogenicity may be dampened by an overabundance of refractory immunosuppressive populations, and support the continued development of SBRT/immunotherapy combination for human PDAC.

Achievable Performance of Uncooled Homojunction GeSn Mid-Infrared Photodetectors

Abstract: Ge1-xSnx photodetectors (PDs) have emerged as a new type of mid-infrared (MIR) CMOS-compatible PDs for a wide range of applications. Here we present a comprehensive theoretical study to evaluate the achievable performance of Ge1-xSnx p-i-n homojunction PDs with strain-free and defect-free Ge1-xSnx active layer for the purpose of demonstrating its potential in advancing the MIR detection technology. Starting from the Sn-composition-dependent band structures, the theoretical model calculates optical absorption, responsivity, dark current density, and detectivity. The results show that the optical responsivity can be enhanced with the Sn incorporation due to the improved optical absorption and the large mobilities and diffusion lengths of the photo-generated electrons and holes. The dark current density, however, increases with the increasing Sn composition. Our model suggests that not only the photodetection range of the Ge1-xSnx PDs can be extended to the MIR region but their detectivity at room temperature can be competitive with the existing MIR technology, and in some cases better than some commercial PDs operating at lower temperatures. This study establishes the ultimate performance that can be potentially achieved with the Ge1-xSnx MIR technology with the maturity of its material development in due time in addition to its much anticipated CMOS-compatible advantages.

A National Study to Assess Validity and Psychometrics of the Short Kessler Psychological Distress Scale (K6)

Abstract: This study aimed to test the validity and reliability of the Kessler Psychological Distress Scale-6 (K6) with a nationally representative clinical sample with various mental health disorders. The c...

A neuromarker for drug and food craving distinguishes drug users from non-users

Abstract: Craving is a core feature of substance use disorders. It is a strong predictor of substance use and relapse and is linked to overeating, gambling, and other maladaptive behaviors. Craving is measured via self-report, which is limited by introspective access and sociocultural contexts. Neurobiological markers of craving are both needed and lacking, and it remains unclear whether craving for drugs and food involve similar mechanisms. Across three functional magnetic resonance imaging studies (n = 99), we used machine learning to identify a cross-validated neuromarker that predicts self-reported intensity of cue-induced drug and food craving (P < 0.0002). This pattern, which we term the Neurobiological Craving Signature (NCS), includes ventromedial prefrontal and cingulate cortices, ventral striatum, temporal/parietal association areas, mediodorsal thalamus and cerebellum. Importantly, NCS responses to drug versus food cues discriminate drug users versus non-users with 82% accuracy. The NCS is also modulated by a self-regulation strategy. Transfer between separate neuromarkers for drug and food craving suggests shared neurobiological mechanisms. Future studies can assess the discriminant and convergent validity of the NCS and test whether it responds to clinical interventions and predicts long-term clinical outcomes. Craving—the urge to use a drug or to eat—is a core feature of substance use disorders. Koban et al. present an fMRI-based and machine-learning-based neuromarker that predicts the intensity of drug and food craving and separates drug users from non-users.

An ultra-dynamic anion-cluster-based organic framework

Abstract: •Anion clusters directed formation of porous molecular crystals •SCSC synthesis of a cross-linked organic framework •HCOF-6 rapidly expand and contract upon phenol uptaking and removal •The dynamics of HCOF-6 comes from the in situ (de)formation of anion clusters Porous organic frameworks that can dynamically expand their voids to guest uptake remain formidable to design. The challenge comes from finding the balance between rigidity and flexibility. Rigidity is required to retain the framework, and the flexibility is needed for reversible expansion/contraction. Herein, we introduced bisulfate anion clusters as soft joints to construct a single-crystalline hydrogen-bonded cross-linked organic framework HCOF-6. Upon the uptake of guest molecules, the anion clusters of HCOF-6 were disrupted, allowing the crystal to expand rapidly (<40 min) to more than twice its original length. Removing these guests restored the anion clusters and the crystallinity of HCOF-6 quickly (<10 min). These guest-induced material size expansions and contractions are highly reversible, and the dynamic anion cluster dissociation-reassociation is confirmed by molecular dynamics simulations and solid-state NMR experiments. The guest-induced size change of HCOF-6 highlights a new approach to synthesize dynamic framework materials by introducing anion clusters. Porous organic frameworks that can dynamically expand their voids to guest uptake remain formidable to design. The challenge comes from finding the balance between rigidity and flexibility. Rigidity is required to retain the framework, and the flexibility is needed for reversible expansion/contraction. Herein, we introduced bisulfate anion clusters as soft joints to construct a single-crystalline hydrogen-bonded cross-linked organic framework HCOF-6. Upon the uptake of guest molecules, the anion clusters of HCOF-6 were disrupted, allowing the crystal to expand rapidly (<40 min) to more than twice its original length. Removing these guests restored the anion clusters and the crystallinity of HCOF-6 quickly (<10 min). These guest-induced material size expansions and contractions are highly reversible, and the dynamic anion cluster dissociation-reassociation is confirmed by molecular dynamics simulations and solid-state NMR experiments. The guest-induced size change of HCOF-6 highlights a new approach to synthesize dynamic framework materials by introducing anion clusters.

Transport of a self-propelled tracer through a hairy cylindrical channel: interplay of stickiness and activity

Abstract: Active transport of biomolecules assisted by motor proteins is imperative for the proper functioning of cellular activities. Inspired by the diffusion of active agents in crowded cellular channels, we computationally investigate the transport of an active tracer through a polymer grafted cylindrical channel by varying the activity of the tracer and stickiness of the tracer to the polymers. Our results reveal that the passive tracer exhibits profound subdiffusion with increasing stickiness by exploring deep into the grafted polymeric zone, while purely repulsive one prefers to diffuse through the pore-like space created along the cylindrical axis of the channel. In contrast, the active tracer shows faster dynamics and intermediate superdiffusion even though the tracer preferentially stays close to the dense polymeric region. This observation is further supported by the sharp peaks in the density profile of the probability of radial displacement of the tracer. We discover that the activity plays an important role in deciding the pathway that the tracer takes through the narrow channel. Interestingly, increasing the activity washes out the effect of stickiness. Adding to this, van-Hove functions manifest that the active tracer dynamics deviates from Gaussianity, and the degree of deviation grows with the activity. Our work has direct implications on how effective transportation and delivery of cargo can be achieved through a confined medium where activity, interactions, and crowding are interplaying. Looking ahead, these factors will be crucial for understanding the mechanism of artificial self-powered machines navigating through the cellular channels and performing in vivo challenging tasks.

Integrated vs nonintegrated treatment for perinatal opioid use disorder: retrospective cohort study

Abstract: BACKGROUND Pregnant women with opioid use disorder and their infants often experience worse perinatal outcomes than women without opioid use disorder, including longer hospitalizations after delivery and a higher risk for preterm delivery. Integrated treatment models, which combine addiction treatment and maternity care, represent an innovative approach that is widely endorsed, however, limited studies have compared the outcomes between integrated and standard, nonintegrated programs from real-world programs. OBJECTIVE This study aimed to evaluate the perinatal and substance use outcomes for pregnant women with opioid use disorder receiving coordinated, colocated obstetrical care and opioid use disorder treatment (integrated treatment) and to compare it with those of women receiving obstetrical care and opioid use disorder treatment in distinct programs of care (nonintegrated treatment). STUDY DESIGN In this observational, retrospective cohort study, we abstracted the perinatal and opioid use disorder treatment data from the records of pregnant women with opioid use disorder (n=225) who delivered at a rural, academic medical center from 2015 to 2017. The women either received integrated (n=92) or nonintegrated (n=133) opioid use disorder treatment and obstetrical care. Using inverse probability weighted regression models to adjust for a potential covariate imbalance, we evaluated the impact of the treatment model on the risk for preterm delivery and positive meconium or umbilical cord toxicology screens. We explored whether the number of obstetrical visits mediated this relationship by using a quasi-Bayesian Monte Carlo algorithm. RESULTS Women receiving integrated treatment were less likely to deliver prematurely (11.8% vs 26.6%; P CONCLUSION Among a cohort of rural pregnant women with opioid use disorder, receiving integrated obstetrical care and opioid use disorder treatment was associated with a reduced risk for preterm birth, a lower risk for positive maternal urine toxicology screen at the time of delivery, and shorter infant hospitalization. This relationship was mediated by the number of obstetrical visits attended during pregnancy, suggesting that increased engagement with obstetrical care through integration of services may contribute to improved perinatal outcomes.

Modeling oil biodegradation and bioremediation within beaches

Abstract: Modeling oil biodegradation and remediation has become an increasingly important means to predict oil persistence and explore potential in-situ bioremediation strategies for oil-contaminated beaches. Beaches involve complex mixing dynamics between seawater and groundwater. Thus, numerically predicting oil biodegradation within beach systems faces major challenges in merging highly dynamic biogeochemical conditions into microbial degradation models. In this paper, we reviewed recent advances in modeling oil biodegradation from aspects of oil phases, reaction kinetics, microbial activities, environmental conditions, and beach hydrodynamics. We identified key controlling factors of oil biodegradation, highlighted the importance of fate and transport processes on nearshore oil biodegradation, and suggested some advances needed to achieve for developing a robust numerical model to predict oil biodegradation and bioremediation within beaches.

Multispecies biofilm architecture determines bacterial exposure to phages

Abstract: Numerous ecological interactions among microbes-for example, competition for space and resources, or interaction among phages and their bacterial hosts-are likely to occur simultaneously in multispecies biofilm communities. While biofilms formed by just a single species occur, multispecies biofilms are thought to be more typical of microbial communities in the natural environment. Previous work has shown that multispecies biofilms can increase, decrease, or have no measurable impact on phage exposure of a host bacterium living alongside another species that the phages cannot target. The reasons underlying this variability are not well understood, and how phage-host encounters change within multispecies biofilms remains mostly unexplored at the cellular spatial scale. Here, we study how the cellular scale architecture of model 2-species biofilms impacts cell-cell and cell-phage interactions controlling larger scale population and community dynamics. Our system consists of dual culture biofilms of Escherichia coli and Vibrio cholerae under exposure to T7 phages, which we study using microfluidic culture, high-resolution confocal microscopy imaging, and detailed image analysis. As shown previously, sufficiently mature biofilms of E. coli can protect themselves from phage exposure via their curli matrix. Before this stage of biofilm structural maturity, E. coli is highly susceptible to phages; however, we show that these bacteria can gain lasting protection against phage exposure if they have become embedded in the bottom layers of highly packed groups of V. cholerae in co-culture. This protection, in turn, is dependent on the cell packing architecture controlled by V. cholerae biofilm matrix secretion. In this manner, E. coli cells that are otherwise susceptible to phage-mediated killing can survive phage exposure in the absence of de novo resistance evolution. While co-culture biofilm formation with V. cholerae can confer phage protection to E. coli, it comes at the cost of competing with V. cholerae and a disruption of normal curli-mediated protection for E. coli even in dual species biofilms grown over long time scales. This work highlights the critical importance of studying multispecies biofilm architecture and its influence on the community dynamics of bacteria and phages.

Whole-brain opto-fMRI map of mouse VTA dopaminergic activation reflects structural projections with small but significant deviations

Abstract: Ascending dopaminergic projections from neurons located in the Ventral Tegmental Area (VTA) are key to the etiology, dysfunction, and control of motivation, learning, and addiction. Due to the evolutionary conservation of this nucleus and the extensive use of mice as disease models, establishing an assay for VTA dopaminergic signaling in the mouse brain is crucial for the translational investigation of motivational control as well as of neuronal function phenotypes for diseases and interventions. In this article we use optogenetic stimulation directed at VTA dopaminergic neurons in combination with functional Magnetic Resonance Imaging (fMRI), a method widely used in human deep brain imaging. We present a comprehensive assay producing the first whole-brain opto-fMRI map of dopaminergic activation in the mouse, and show that VTA dopaminergic system function is consistent with its structural VTA projections, diverging only in a few key aspects. While the activation map predominantly highlights target areas according to their relative projection densities (e.g., strong activation of the nucleus accumbens and low activation of the hippocampus), it also includes areas for which a structural connection is not well established (such as the dorsomedial striatum). We further detail the variability of the assay with regard to multiple experimental parameters, including stimulation protocol and implant position, and provide evidence-based recommendations for assay reuse, publishing both reference results and a reference analysis workflow implementation.

Motion of an active particle with dynamical disorder

Abstract: We propose a model for investigating the motion of a single active particle in a heterogeneous environment where the heterogeneity may arise due to crowding, conformational fluctuations and/or slow rearrangement of the surroundings. Describing the active particle in terms of the Ornstein-Uhlenbeck process (OUP) and incorporating heterogeneity in a thermal bath using two separate models, namely "diffusing diffusivity" and "switching diffusion", we explore the essential dynamical properties of the particle for its one-dimensional motion. In addition, we show how the dynamical behavior is controlled by dynamical variables associated with active noise such as strength and persistence time. Our model is relevant in the context of single particle dynamics in a crowded environment, driven by activity.

Chemically symmetric and asymmetric self-driven rigid dumbbells in a 2D polymer gel

Abstract: We employ computer simulations to unveil the translational and rotational dynamics of self-driven chemically symmetric and asymmetric rigid dumbbells in a two-dimensional polymer gel. Our results show that the activity or the self-propulsion always enhances the dynamics of the dumbbells. Making the self-propelled dumbbell chemically asymmetric leads to further enhancement in dynamics. Additionally, the direction of self-propulsion is a key factor for chemically asymmetric dumbbells, where self-propulsion towards the non-sticky half of the dumbbell results in faster translational and rotational dynamics compared to the case with the self-propulsion towards the sticky half of the dumbbell. Our analyses show that both the symmetric and asymmetric passive rigid dumbbells get trapped inside the mesh of the polymer gel, but the chemical asymmetry always facilitates the mesh to mesh motion of the dumbbell and it is even more pronounced when the dumbbell is self-propelled. This results in multiple peaks in the van Hove function with increasing self-propulsion. In a nutshell, we believe that our in silico study can guide researchers to design efficient artificial microswimmers possessing potential applications in site-specific delivery.

Small molecules targeting the disordered transactivation domain of the androgen receptor induce the formation of collapsed helical states

Abstract: Intrinsically disordered proteins, which do not adopt well-defined structures under physiological conditions, are implicated in many human diseases. Small molecules that target the disordered transactivation domain of the androgen receptor have entered human trials for the treatment of castration-resistant prostate cancer (CRPC), but no structural or mechanistic rationale exists to explain their inhibition mechanisms or relative potencies. Here, we utilize all-atom molecular dynamics computer simulations to elucidate atomically detailed binding mechanisms of the compounds EPI-002 and EPI-7170 to the androgen receptor. Our simulations reveal that both compounds bind at the interface of two transiently helical regions and induce the formation of partially folded collapsed helical states. We find that EPI-7170 binds androgen receptor more tightly than EPI-002 and we identify a network of intermolecular interactions that drives higher affinity binding. Our results suggest strategies for developing more potent androgen receptor inhibitors and general strategies for disordered protein drug design.