Author Correction: Design of amidobenzimidazole STING receptor agonists with systemic activity.

Change history: In this Letter, author Ana Puhl was inadvertently omitted; this error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Lead Time and Immortal Time Biases Impact the Calculation of Post-colonoscopy Colorectal Cancer Survival.

The World Endoscopy Organization (WEO) standardized the reporting of post-colonoscopy colorectal cancers (PCCRCs), which account for 7% to 10% of colorectal cancers (CRCs).1 PCCRCs are diagnosed 6 to 36 months after a false negative colonoscopy. Detected CRCs (dCRCs) are diagnosed ≤6 months after an index true positive colonoscopy.2 PCCRC prognosis is unclear, with outcomes reported as comparable,3 superior,4 or inferior5,6 to those of dCRC. Because WEO terminology defines cases relative to the index colonoscopy, conventional survival analyses of PCCRC are susceptible to lead time and immortal time biases. We evaluated the influence of these biases on mortality in a population-based retrospective cohort of 10,938 dCRCs (93.8%) and 717 PCCRCs (6.2%). This study was set within Kaiser Permanente Northern California (KPNC), a large integrated health system, whose members are similar in demographic and socioeconomic characteristics to the Northern California region.7.

Infraorbital nerve injury triggers sex-specific neuroimmune responses in the peripheral trigeminal pathway and common pain behaviours.

Trigeminal neuropathic pain is emotionally distressing and disabling. It presents with allodynia, hyperalgesia and dysaesthesia. In preclinical models it has been assumed that cephalic nerve constriction injury shows identical molecular, cellular, and sex dependent neuroimmune changes as observed in extra-cephalic injury models. This study sought empirical evidence for such assumptions using the infraorbital nerve chronic constriction model (ION-CCI). We compared the behavioural consequences of nerve constriction with: (i) the temporal patterns of recruitment of macrophages and T-lymphocytes at the site of nerve injury and in the trigeminal ganglion; and (ii) the degree of demyelination and axonal reorganisation in the injured nerve. Our data demonstrated that simply testing for allodynia and hyperalgesia as is done in extra-cephalic neuropathic pain models does not provide access to the range of injury-specific nociceptive responses and behaviours reflective of the experience of trigeminal neuropathic pain. Similarly, trigeminal neuroimmune changes evoked by nerve injury are not the same as those identified in models of extra-cephalic neuropathy. Specifically, the timing, magnitude, and pattern of ION-CCI evoked macrophage and T-lymphocyte activity differs between the sexes.

Design of amidobenzimidazole STING receptor agonists with systemic activity.

Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA1. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants2. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery3. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. Intravenous administration of a diABZI STING agonist to immunocompetent mice with established syngeneic colon tumours elicited strong anti-tumour activity, with complete and lasting regression of tumours. Our findings represent a milestone in the rapidly growing field of immune-modifying cancer therapies.

Biological Therapeutic Modalities for Intervertebral Disc Diseases: An Orthoregeneration Network (ON) Foundation Review.

Orthoregeneration is defined as a solution for orthopaedic conditions that harnesses the benefits of biology to improve healing, reduce pain, improve function, and, optimally, provide an environment for tissue regeneration. Options include drugs, surgical intervention, scaffolds, biologics as a product of cells, and physical and electromagnetic stimuli. The goal of regenerative medicine is to enhance the healing of tissue after musculoskeletal injuries as both isolated treatment and adjunct to surgical management, using novel therapies to improve recovery and outcomes. Various orthopaedic biologics (orthobiologics) have been investigated for the treatment of pathology involving the spine, including lower back pain, with or without numbness and/or dysfunction in the lower extremities, disc herniation, spinal stenosis, and spondylolisthesis. Promising and established treatment modalities include repair of the annulus fibrosis, injection of expanded or nonexpanded autologous or allogenic cells that are chondrogenic or from a stem cell lineage used to promote matrix tissue regeneration of the intervertebral disc, including nucleus pulpous cells and mesenchymal stem cells isolated from bone marrow, umbilical cord blood, or adipose tissue; and injection of platelet-rich plasma, platelet-rich fibrin, or fibrin sealant. Early clinical studies show promise for pain reduction and functional recovery. LEVEL OF EVIDENCE: Level V, expert opinion.

Serotonin and Dopamine Show Different Response Profiles to Acute Stress in the Nucleus Accumbens and Medial Prefrontal Cortex of Rats with Neuropathic Pain.

The ability to adaptively guide behaviour requires the integration of external information with internal motivational factors. Decision-making capabilities can be impaired by acute stress and is often exacerbated by chronic pain. Chronic neuropathic pain patients often present with cognitive dysfunction, including impaired decision-making. The mechanisms underlying these changes are not well understood but may include altered monoaminergic transmission in the brain. In this study we investigated the relationships between dopamine, serotonin, and their metabolites in key brain regions that regulate motivated behaviour and decision-making. The neurochemical profiles of the medial prefrontal cortex, orbital prefrontal cortex, and nucleus accumbens were analysed using HPLC in rats that received a chronic constriction injury (CCI) of the right sciatic nerve and an acute stress (15-min restraint), prior to an outcome devaluation task. CCI alone significantly decreased dopamine but not serotonin concentrations in the medial prefrontal cortex. By contrast, restraint stress acutely increased dopamine in the medial prefrontal cortex, and the nucleus accumbens; and increased serotonin in the medial prefrontal cortex 2 h later. The sustained dopaminergic and serotonergic responses to acute stress highlight the importance of an animal's ability to mount an effective coping response. In addition, these data suggest that the impact of nerve injury and acute stress on outcome-devaluation occurs independently of dopaminergic and serotonergic transmission in the medial prefrontal cortex, orbital prefrontal cortex and nucleus accumbens of rats.

Experiences of Patients Taking Conditioned Open-Label Placebos for Reduction of Postoperative Pain and Opioid Exposure After Spine Surgery.

BACKGROUND: Pain after spine surgery is difficult to manage, often requiring the use of opioid analgesics. While traditional "deceptive" or concealed placebo has been studied in trials and laboratory experiments, the acceptability and patient experience of taking honestly prescribed placebos, such as "open-label" placebo (non-deceptive placebo), or conditioned placebo (pairing placebo with another active pharmaceutical) is relatively unexamined. METHODS: Qualitative thematic analysis was performed using semi-structured, post-treatment interviews with spine surgery patients (n = 18) who had received conditioned open-label placebo (COLP) during the first 2-3 weeks after surgery as part of a RCT. Interview transcripts were reviewed by 3 investigators using an immersion/crystallization approach, followed by iterative large-group discussions with additional investigators, to identify, refine, and codify emergent themes. RESULTS: Patients' experiences and perceptions of COLP efficacy varied widely. Some emergent themes included the power of the mind over pain, how COLP might provide distraction from or agency over pain, bandwidth required and engagement with COLP, and its modulation of opioid tapering, as well as negative attitudes toward opioids and pill taking in general. Other themes included uncertainty about COLP efficacy, observations of how personality may relate to COLP efficacy, and a recognition of the greater impact of COLP on reduction of opioid use rather than on pain itself. Interestingly, participant uncertainty, disbelief, and skepticism were not necessarily associated with greater opioid consumption or worse pain. CONCLUSION: Participants provided insights into the experience of COLP which may help to guide its future utilization to manage acute pain and tapering from opioids.

Nafion Modified Titanium Nitride pH Sensor for Future Biomedical Applications.

pH sensors are increasingly being utilized in the biomedical field and have been implicated in health applications that aim to improve the monitoring and treatment of patients. In this work, a previously developed Titanium Nitride (TiN) solid-state pH sensor is further enhanced, with the potential to be used for pH regulation inside the human body and for other biomedical, industrial, and environmental applications. One of the main limitations of existing solid-state pH sensors is their reduced performance in high redox mediums. The potential shift E0 value of the previously developed TiN pH electrode in the presence of oxidizing or reducing agents is 30 mV. To minimize this redox shift, a Nafion-modified TiN electrode was developed, tested, and evaluated in various mediums. The Nafion-modified electrode has been shown to shift the E0 value by only 2 mV, providing increased accuracy in highly redox samples while maintaining acceptable reaction times. Overcoming the redox interference for pH measurement enables several advantages of the Nafion-modified TiN electrode over the standard pH glass electrode, implicating its use in medical diagnosis, real-time health monitoring, and further development of miniaturized smart sensors.

A Comprehensive Review on Machine Learning in Healthcare Industry: Classification, Restrictions, Opportunities and Challenges.

Recently, various sophisticated methods, including machine learning and artificial intelligence, have been employed to examine health-related data. Medical professionals are acquiring enhanced diagnostic and treatment abilities by utilizing machine learning applications in the healthcare domain. Medical data have been used by many researchers to detect diseases and identify patterns. In the current literature, there are very few studies that address machine learning algorithms to improve healthcare data accuracy and efficiency. We examined the effectiveness of machine learning algorithms in improving time series healthcare metrics for heart rate data transmission (accuracy and efficiency). In this paper, we reviewed several machine learning algorithms in healthcare applications. After a comprehensive overview and investigation of supervised and unsupervised machine learning algorithms, we also demonstrated time series tasks based on past values (along with reviewing their feasibility for both small and large datasets).

Enhanced Heart Rate Prediction Model Using Damped Least-Squares Algorithm.

Monitoring a patient's vital signs is considered one of the most challenging problems in telehealth systems, especially when patients reside in remote locations. Companies now use IoT devices such as wearable devices to participate in telehealth systems. However, the steady adoption of wearables can result in a significant increase in the volume of data being collected and transmitted. As these devices run on limited battery power, they can run out of power quickly due to the high processing requirements of the device for data collection and transmission. Given the importance of medical data, it is imperative that all transmitted data adhere to strict integrity and availability requirements. Reducing the volume of healthcare data and the frequency of transmission can improve a device's battery life via an inference algorithm. Furthermore, this approach creates issues for improving transmission metrics related to accuracy and efficiency, which are traded-off against each other, with increasing accuracy reducing efficiency. This paper demonstrates that machine learning (ML) can be used to overcome the trade-off problem. The damped least-squares algorithm (DLSA) is used to enhance both metrics by taking fewer samples for transmission whilst maintaining accuracy. The algorithm is tested with a standard heart rate dataset to compare the metrics. The results showed that the DLSA provides the best performance, with an efficiency of 3.33 times for reduced sample data size and an accuracy of 95.6%, with similar accuracies observed in seven different sampling cases adopted for testing that demonstrate improved efficiency. This proposed method significantly improve both metrics using ML without sacrificing one metric over the other compared to existing methods with high efficiency.

ISSLS prize in basic science 2021: a novel inducible system to regulate transgene expression of TIMP1.

PURPOSE: Inflammatory and oxidative stress upregulates matrix metalloproteinase (MMP) activity, leading to intervertebral disc degeneration (IDD). Gene therapy using human tissue inhibitor of metalloproteinase 1 (hTIMP1) has effectively treated IDD in animal models. However, persistent unregulated transgene expression may have negative side effects. We developed a recombinant adeno-associated viral (AAV) gene vector, AAV-NFκB-hTIMP1, that only expresses the hTIMP1 transgene under conditions of stress. METHODS: Rabbit disc cells were transfected or transduced with AAV-CMV-hTIMP1, which constitutively expresses hTIMP1, or AAV-NFκB-hTIMP1. Disc cells were selectively treated with IL-1ß. NFκB activation was verified by nuclear translocation. hTIMP1 mRNA and protein expression were measured by RT-PCR and ELISA, respectively. MMP activity was measured by following cleavage of a fluorogenic substrate. RESULTS: IL-1ß stimulation activated NFκB demonstrating that IL-1ß was a surrogate for inflammatory stress. Stimulating AAV-NFκB-hTIMP1 cells with IL-1ß increased hTIMP1 expression compared to unstimulated cells. AAV-CMV-hTIMP1 cells demonstrated high levels of hTIMP1 expression regardless of IL-1ß stimulation. hTIMP1 expression was comparable between IL-1ß stimulated AAV-NFκB-hTIMP1 cells and AAV-CMV-hTIMP1 cells. MMP activity was decreased in AAV-NFκB-hTIMP1 cells compared to baseline levels or cells exposed to IL-1ß. CONCLUSION: AAV-NFκB-hTIMP1 is a novel inducible transgene delivery system. NFκB regulatory elements ensure that hTIMP1 expression occurs only with inflammation, which is central to IDD development. Unlike previous inducible systems, the AAV-NFκB-hTIMP1 construct is dependent on endogenous factors, which minimizes potential side effects caused by constitutive transgene overexpression. It also prevents the unnecessary production of transgene products in cells that do not require therapy.

Assessing the quality of shared decision making for elective orthopedic surgery across a large healthcare system: cross-sectional survey study.

BACKGROUND: Clinical guidelines recommend engaging patients in shared decision making for common orthopedic procedures; however, limited work has assessed what is occurring in practice. This study assessed the quality of shared decision making for elective hip and knee replacement and spine surgery at four network-affiliated hospitals. METHODS: A cross-sectional sample of 875 adult patients undergoing total hip or knee joint replacement (TJR) for osteoarthritis or spine surgery for lumbar herniated disc or lumbar spinal stenosis was selected. Patients were mailed a survey including measures of Shared Decision Making (SDMP scale) and Informed, Patient-Centered (IPC) decisions. We examined decision-making across sites, surgeons, and conditions, and whether the decision-making measures were associated with better health outcomes. Analyses were adjusted for clustering of patients within surgeons. RESULTS: Six hundred forty-six surveys (74% response rate) were returned with sufficient responses for analysis. Patients who had TJR reported lower SDMP scores than patients who had spine surgery (2.2 vs. 2.8; p < 0.001). Patients who had TJR were more likely to make IPC decisions (OA = 70%, Spine = 41%; p < 0.001). SDMP and IPC scores varied widely across surgeons, but the site was not predictive of SDMP scores or IPC decisions (all p > 0.09). Higher SDMP scores and IPC decisions were associated with larger improvements in global health outcomes for patients who had TJR, but not patients who had spine surgery. CONCLUSIONS: Measures of shared decision making and decision quality varied among patients undergoing common elective orthopedic procedures. Routine measurement of shared decision making provides insight into areas of strength across these different orthopedic conditions as well as areas in need of improvement.

Improving Arthroplasty Efficiency and Quality Through Concentrating Service Volume by Complexity: Surviving the Medicare Policy Changes.

We have an academic medical center (AMC), an associated community-based hospital (CBH) and several ambulatory care centers which are being prepared to provide same day discharge (SDD) total joint arthroplasty (TJA) and unicompartmental knee arthroplasty (UKA). The near-capacity AMC cared for medically and technically complicated TJA patients. The CBH wanted to increase volume, improve margins, and become a center of excellence with an efficient hospital outpatient department and SDD TJA experience. METHODS: We transitioned primary, uncomplicated TJA, UKA, and minimally invasive TJA to the CBH. Revision surgeries, patients with extensive comorbidities, and complex primaries were performed at the AMC. Protocols were developed to facilitate SDD UKA and total hip arthroplasty (THA) as well as rapid recovery protocols for total knee arthroplasty (TKA) at both hospitals. A protocol-based system was put in place to make both hospitals ready for the removal of TKA from the Inpatient-Only list to avoid Quality Improvement Organization and possible resultant Recovery Audit Contractor audits if referred after implementation. RESULTS: The CBH volume increased 36.7% (+239). AMC volume slightly decreased (-0.46%, -5) resulting in an increase in margin contribution for the system. CBH quality metrics (surgical site infections, length of stay, readmissions, and mortality) were improved. Surgeon satisfaction improved as their volume, efficiency, quality metrics, and finances were enhanced. Although CBH per case revenue was 80.3% and 74.4% of the AMC for THA and TKA, net margins were 3.6% and 18.8% higher for THA and TKA, respectively. Increased efficiency, lower hospital cost, and higher volume at the CBH allowed for an increase in revenue despite lower reimbursement per case. CONCLUSION: This strategy will help hospital systems improve net margins while improving patient care despite lower net revenue per TJA episode. These strategies will become increasingly important going forward with the transition of higher numbers of TJA patients to outpatient which will be subjected to further decreases in net revenue per patient.

An Energy-Efficient and Secure Data Inference Framework for Internet of Health Things: A Pilot Study.

Privacy protection in electronic healthcare applications is an important consideration, due to the sensitive nature of personal health data. Internet of Health Things (IoHT) networks that are used within a healthcare setting have unique challenges and security requirements (integrity, authentication, privacy, and availability) that must also be balanced with the need to maintain efficiency in order to conserve battery power, which can be a significant limitation in IoHT devices and networks. Data are usually transferred without undergoing filtering or optimization, and this traffic can overload sensors and cause rapid battery consumption when interacting with IoHT networks. This poses certain restrictions on the practical implementation of these devices. In order to address these issues, this paper proposes a privacy-preserving two-tier data inference framework solution that conserves battery consumption by inferring the sensed data and reducing data size for transmission, while also protecting sensitive data from leakage to adversaries. The results from experimental evaluations on efficiency and privacy show the validity of the proposed scheme, as well as significant data savings without compromising data transmission accuracy, which contributes to energy efficiency of IoHT sensor devices.

Classification of Skin Disease Using Deep Learning Neural Networks with MobileNet V2 and LSTM.

Deep learning models are efficient in learning the features that assist in understanding complex patterns precisely. This study proposed a computerized process of classifying skin disease through deep learning based MobileNet V2 and Long Short Term Memory (LSTM). The MobileNet V2 model proved to be efficient with a better accuracy that can work on lightweight computational devices. The proposed model is efficient in maintaining stateful information for precise predictions. A grey-level co-occurrence matrix is used for assessing the progress of diseased growth. The performance has been compared against other state-of-the-art models such as Fine-Tuned Neural Networks (FTNN), Convolutional Neural Network (CNN), Very Deep Convolutional Networks for Large-Scale Image Recognition developed by Visual Geometry Group (VGG), and convolutional neural network architecture that expanded with few changes. The HAM10000 dataset is used and the proposed method has outperformed other methods with more than 85% accuracy. Its robustness in recognizing the affected region much faster with almost 2× lesser computations than the conventional MobileNet model results in minimal computational efforts. Furthermore, a mobile application is designed for instant and proper action. It helps the patient and dermatologists identify the type of disease from the affected region's image at the initial stage of the skin disease. These findings suggest that the proposed system can help general practitioners efficiently and effectively diagnose skin conditions, thereby reducing further complications and morbidity.

Augmented Chondroitin Sulfate Proteoglycan Has Therapeutic Potential for Intervertebral Disc Degeneration by Stimulating Anabolic Turnover in Bovine Nucleus Pulposus Cells under Changes in Hydrostatic Pressure.

Nucleus pulposus (NP) cells are exposed to changes in hydrostatic pressure (HP) and osmotic pressure within the intervertebral disc. We focused on main disc matrix components, chondroitin sulfate proteoglycan (CSPG) and hyaluronan (HA) to elucidate the capability of augmented CSPG to enhance the anabolism of bovine NP (bNP) cells under repetitive changes in HP at high osmolality. Aggrecan expression with CSPG in the absence of HP was significantly upregulated compared to the no-material control (phosphate buffer saline) under no HP at 3 days, and aggrecan expression with CSPG under HP was significantly higher than the control with HA under HP at 12 days. Collagen type I expression under no HP was significantly lower with CSPG than in controls at 3 days. Although matrix metalloproteinase 13 expression under HP was downregulated compared to no HP, it was significantly greater with HA than the control and CSPG, even under HP. Immunohistology revealed the involvement of mechanoreceptor of transient receptor potential vanilloid-4 activation under HP, suggesting an HP transduction mechanism. Addition of CSPG had anabolic and anti-fibrotic effects on bNP cells during the early culture period under no HP; furthermore, it showed synergy with dynamic HP to increase bNP-cell anabolism at later time points.

Brief Preoperative Screening for Frailty and Cognitive Impairment Predicts Delirium after Spine Surgery.

BACKGROUND: Frailty and cognitive impairment are associated with postoperative delirium, but are rarely assessed preoperatively. The study was designed to test the hypothesis that preoperative screening for frailty or cognitive impairment identifies patients at risk for postoperative delirium (primary outcome). METHODS: In this prospective cohort study, the authors administered frailty and cognitive screening instruments to 229 patients greater than or equal to 70 yr old presenting for elective spine surgery. Screening for frailty (five-item FRAIL scale [measuring fatigue, resistance, ambulation, illness, and weight loss]) and cognition (Mini-Cog, Animal Verbal Fluency) were performed at the time of the preoperative evaluation. Demographic data, perioperative variables, and postoperative outcomes were gathered. Delirium was the primary outcome detected by either the Confusion Assessment Method, assessed daily from postoperative day 1 to 3 or until discharge, if patient was discharged sooner, or comprehensive chart review. Secondary outcomes were all other-cause complications, discharge not to home, and hospital length of stay. RESULTS: The cohort was 75 [73 to 79 yr] years of age, 124 of 219 (57%) were male. Many scored positive for prefrailty (117 of 218; 54%), frailty (53 of 218; 24%), and cognitive impairment (50 to 82 of 219; 23 to 37%). Fifty-five patients (25%) developed delirium postoperatively. On multivariable analysis, frailty (scores 3 to 5 [odds ratio, 6.6; 95% CI, 1.96 to 21.9; P = 0.002]) versus robust (score 0) on the FRAIL scale, lower animal fluency scores (odds ratio, 1.08; 95% CI, 1.01 to 1.51; P = 0.036) for each point decrease in the number of animals named, and more invasive surgical procedures (odds ratio, 2.69; 95% CI, 1.31 to 5.50; P = 0.007) versus less invasive procedures were associated with postoperative delirium. CONCLUSIONS: Screening for frailty and cognitive impairment preoperatively using the FRAIL scale and the Animal Verbal Fluency test in older elective spine surgery patients identifies those at high risk for the development of postoperative delirium.

Ambulatory status after surgical and nonsurgical treatment for spinal metastasis.

BACKGROUND: Decisions for operative or nonoperative management remain challenging for patients with spinal metastases, especially when life expectancy and quality of life are not easily predicted. This study evaluated the effects of operative and nonoperative management on maintenance of ambulatory function and survival for patients treated for spinal metastases. METHODS: Propensity matching was used to yield an analytic sample in which operatively and nonoperatively treated patients were similar with respect to key baseline covariates. The study included patients treated for spinal metastases between 2005 and 2017 who were 40 to 80 years old, were independent ambulators at presentation, and had fewer than 5 medical comorbidities. It evaluated the influence of operative care and nonoperative care on ambulatory function 6 months after presentation as the primary outcome. Survival at 6 months and survival at 1 year were secondary outcomes. RESULTS: Nine hundred twenty-nine individuals eligible for inclusion were identified, with 402 (201 operative patients and 201 nonoperative patients) retained after propensity score matching. Patients treated operatively had a lower likelihood than those treated nonoperatively of being nonambulatory 6 months after presentation (3% vs 16%; relative risk [RR], 0.16; 95% confidence interval [CI], 0.06-0.46) as well as a reduced risk of 6-month mortality (20% vs 29%; RR, 0.69; 95% CI, 0.49-0.98). CONCLUSIONS: These results indicate that in a group of patients with similar demographic and clinical characteristics, those treated operatively were less likely to lose ambulatory function 6 months after presentation than those managed nonoperatively. For patients with spinal metastases, our data can be incorporated into discussions about the treatments that align best with patients' preferences regarding surgical risk, mortality, and ambulatory status.

Altered monoamine levels in the dorsal striatum of the rat are associated with alterations in behavioural selection and motivation following peripheral nerve injury and acute stress.

Chronic neuropathic pain and psychological stress interact to compromise goal-directed control over behaviour following mild psychological stress. The dorsomedial (DMS) and dorsolateral (DLS) striatum in the rat are crucial for the expression of goal-directed and habitual behaviours, respectively. This study investigated whether changes in monoamine levels in the DMS and DLS following nerve injury and psychological stress reflect these behavioural differences. Neuropathic pain was induced by a chronic constriction injury (CCI) of the sciatic nerve in Sprague-Dawley rats. Acute stress was induced using a 15-min restraint. Behavioural flexibility was assessed using the outcome devaluation paradigm. Noradrenaline, serotonin, dopamine and associated metabolites were measured bilaterally from the DLS and DMS. In uninjured rats, restraint increased dopaminergic markers in the left and serotonergic markers in the right of both the DMS and DLS, indicating a possible left hemisphere-mediated dominance. CCI led to a slightly different lateralised effect, with a larger effect in the DMS than in the DLS. Individual differences in behavioural flexibility following CCI negatively correlated with dopaminergic markers in the right DLS, but positively correlated with these markers in the left DMS. A combination of CCI and restraint reduced behavioural flexibility, which was associated with the loss of the left/DMS dominance. These data suggest that behavioural flexibility following psychological stress or pain is associated with a left hemisphere dominance within the dorsal striatum. The loss of behavioural flexibility following the combined stressors is then associated with a transition from left to right, and DMS to DLS dominance.