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Future lunar missions and beyond will require new and innovative approaches to radiation countermeasures. The Translational Research Institute for Space Health (TRISH) is focused on identifying and supporting unique approaches to reduce risks to human health and performance on future missions beyond low Earth orbit. This paper will describe three funded and complementary avenues for reducing the risk to humans from radiation exposure experienced in deep space. The first focus is on identifying new therapeutic targets to reduce the damaging effects of radiation by focusing on high throughput genetic screens in accessible, sometimes called lower, organism models. The second focus is to design innovative approaches for countermeasure development with special attention to nucleotide-based methodologies that may constitute a more agile way to design therapeutics. The final focus is to develop new and innovative ways to test radiation countermeasures in a human model system. While animal studies continue to be beneficial in the study of space radiation, they can have imperfect translation to humans. The use of three-dimensional (3D) complex in vitro models is a promising approach to aid the development of new countermeasures and personalized assessments of radiation risks. These three distinct and unique approaches complement traditional space radiation efforts and should provide future space explorers with more options to safeguard their short and long-term health.

Background Complex Regional Pain Syndrome (CRPS) is a disabling pain disorder that is most common after a distal limb fracture. While the acute systemic immune response to the injury is thought to play a role in the development of CRPS, this hypothesis has never been tested directly. Thus, we evaluated whether elevated levels of circulating pro-inflammatory cytokines early after a fracture were associated with the development of CRPS. Methods We conducted a case-control study nested within a prospective cohort study. Individuals with wrist and/or hand fractures were recruited from specialist hand units. Baseline clinical data were obtained from participants within 28 days of fracture. CRPS status was determined 16 weeks after the fracture using a two-stage diagnostic process. Cytokine assays were obtained from all cases (defined using the Budapest criteria) and a random sample of those who did not have CRPS at 16 weeks. We calculated odds ratios with 95% confidence intervals to determine the risk of CRPS associated with the expression of each of 25 cytokines. Results Baseline data were collected for 702 consenting participants, of whom 535 provided blood samples. Follow-up at 16 weeks was 97.2%. 15 (2.2% of the cohort) met the Budapest CRPS criteria and 69 (including those who met the Budapest criteria; 9.8%) met the International Association for the Study of Pain (IASP) CRPS criteria. In all of the primary analyses (using Budapest criteria) and 49/50 secondary analyses (using IASP criteria), 95% confidence intervals for the association between cytokine levels and the risk of subsequently developing CRPS included the null value (OR = 1). However, the confidence intervals were wide. Conclusion There was no evidence that early post-injury expression of systemic cytokines was associated with a CRPS diagnosis 16 weeks after injury. This study does not provide support for the hypothesis that innate immune activation has a determinative role in the development of CRPS.

Positive social experiences may induce oxytocin release. However, previous studies of moral elevation have generally utilized cross-sectional and simple modeling approaches to establish the relationship between oxytocin and emotional stimuli. Utilizing a cohort of 30 non-lactating women (aged 23.6±5.7 years), we tested whether exposure to a video identified as capable of eliciting moral elevation could change plasma oxytocin levels. Uniquely, we utilized a high-frequency longitudinal sampling approach and multilevel growth curve modeling with landmark registration to test physiological responses. The moral elevation stimulus, versus a control video, elicited significantly greater reports of being "touched/inspired" and "happy/joyful". However, the measured plasma oxytocin response was found to be markedly heterogeneous. While the moral elevation stimulus elicited increased plasma oxytocin as expected, this increase was only modestly larger than that seen following the control video. This increase was also only present in some individuals. We found no relationship between plasma oxytocin and self-report responses to the stimulus. From these data, we argue that future studies of the relationship between oxytocin and emotion need to anticipate heterogeneous responses and thus incorporate comprehensive individual psychological data; these should include evidence-based variables known to be associated with oxytocin such as a history of trauma, and the individual's psychological and emotional state at the time of testing. Given the complexity of physiological oxytocin release, such studies also need to incorporate frequent biological sampling to properly examine the dynamics of hormonal release and response.

The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells (NSCs), are important for learning and memory as well as mood control. During aging, the number and responses of NSCs to neurogenic stimuli diminish, leading to decreased neurogenesis and age-associated cognitive decline and psychiatric disorders. Thus, adult hippocampal neurogenesis has been the subject of intense investigation, generating both excitement and controversy. Identifying the core molecular machinery responsible for NSC preservation is of fundamental importance if we are to use neurogenesis to halt or reverse hippocampal age-related pathology. Here, we briefly overview the most frequently used mouse models to study hippocampal neurogenesis and then focus on a unique mouse model that allows NSC-specific studies based on their unique expression of lunatic fringe (Lfng). The Lfng-eGFP and Lfng(BAC)-CreERT2;RCL-tdT transgenic mice provide us with an excellent tool to resolve long-standing questions regarding the properties of NSCs, such as their specific molecular composition, potency, and plasticity, in isolation from any other cell in the hippocampal neurogenic niche.

Dysregulation of the JAK/STAT signaling pathway is associated with Multiple Sclerosis (MS) and its mouse model, Experimental Autoimmune Encephalomyelitis (EAE). Suppressors Of Cytokine Signaling (SOCS) negatively regulate the JAK/STAT pathway. We previously reported a severe, brain-targeted, atypical form of EAE in mice lacking Socs3 in myeloid cells (Socs3ΔLysM), which is associated with cerebellar neutrophil infiltration. There is emerging evidence that neutrophils are detrimental in the pathology of MS/EAE, however, their exact function is unclear. Here we demonstrate that neutrophils from the cerebellum of Socs3ΔLysM mice show a hyper-activated phenotype with excessive production of reactive oxygen species (ROS) at the peak of EAE. Neutralization of ROS in vivo delayed the onset and reduced severity of atypical EAE. Mechanistically, Socs3-deficient neutrophils exhibit enhanced STAT3 activation, a hyper-activated phenotype in response to G-CSF, and upon G-CSF priming, increased ROS production. Neutralization of G-CSF in vivo significantly reduced the incidence and severity of the atypical EAE phenotype. Overall, our work elucidates that hypersensitivity of G-CSF/STAT3 signaling in Socs3ΔLysM mice leads to atypical EAE by enhanced neutrophil activation and increased oxidative stress, which may explain the detrimental role of G-CSF in MS patients.

Dysregulation of the JAK/STAT signaling pathway is associated with multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Suppressors of cytokine signaling (SOCS) negatively regulate the JAK/STAT pathway. We previously reported a severe, brain-targeted, atypical form of EAE in mice lacking Socs3 in myeloid cells (Socs3(ΔLysM)), and that this atypical EAE is associated with cerebellar neutrophil infiltration. There is emerging evidence that neutrophils are detrimental in the pathology of MS/EAE; however, their exact function is unclear. Here we demonstrate that neutrophils from the cerebellum of Socs3(ΔLysM) mice show a hyperactivated phenotype with excessive production of reactive oxygen species (ROS) at the peak of EAE. Neutralization of ROS in vivo delayed the onset and reduced severity of atypical EAE. Mechanistically, Socs3-deficient neutrophils exhibited enhanced signal transducer and activator of transcription 3 (STAT3) activation, a hyperactivated phenotype in response to granulocyte colony–stimulating factor (G-CSF), and upon G-CSF priming, increased ROS production. Neutralization of G-CSF in vivo significantly reduced the incidence and severity of the atypical EAE phenotype. Overall, our work elucidates that hypersensitivity of G-CSF/STAT3 signaling in Socs3(ΔLysM) mice leads to atypical EAE by enhanced neutrophil activation and increased oxidative stress, which may explain the detrimental role of G-CSF in MS patients.

Worldwide, the incidence of wrist fracture is increasing. There are currently no externally validated prognostic models to inform early decision making for these patients.To develop and validate a prognostic model from a comprehensive range of candidate prognostic factors that can identify patients who are at risk of developing persistent pain following wrist or hand fracture.We developed and validated a prognostic model using secondary data derived from a prospective cohort study (n = 715), with recruitment sites in 3 metropolitan hospitals in Sydney, Australia. The primary outcome was persistent pain 4 months following the injury. The current study used a backward stepwise regression analysis to develop the model in 2 hospitals (n = 408) and externally validate it in a third hospital (n = 307). To determine the accuracy of the model, we assessed calibration and discrimination in accordance with the PROGnosis RESearch Strategy framework.Complete data were available for 95% of the cohort. Of 14 candidate variables, the final model contained 2 prognostic factors: patient age and pain intensity reported at initial presentation. The area under the receiver operating characteristic curve was 0.63 (95% confidence interval: 0.56, 0.69) in the development sample and 0.61 (95% confidence interval: 0.51, 0.70) in the validation sample. The model systematically overestimated risk (intercept, -1.13; slope, 0.73).We developed and externally validated a prognostic model to predict persistent pain 4 months after a wrist or hand fracture. Future studies are needed to assess whether the accuracy of this model can be improved by updating and validating it in local settings.Prognosis, level 1b. J Orthop Sports Phys Ther 2019;49(1):28-35. Epub 12 Sep 2018. doi:10.2519/jospt.2019.8342.

Dysfunction in the central nervous systemis thought to underlie themovement disorders that commonly occur in complex regional pain syndrome (CRPS), with much of the literature focusing on reorganization of the primary motor cortex (M1). Presumed changes in the M1 representation of the CRPS-affected body part have contributed to new CRPS treatments, which are increasingly being integrated in the clinic. We systematically investigated the evidence for altered M1 function in CRPS. We adhered to rigorous systematic review procedure in our search strategy, risk-of-bias appraisal, and data extraction. Eighteen studies comprising 14 unique data sets were included. The included studies used several neuroimaging techniques, whose outcomeswe grouped intoM1 cortical excitability, spatial representation, reactivity, and glucose metabolism, and conducted meta-analyses where possible. Risk of bias across studies was high, mainly due tomissing data and unblinded assessment of outcomes. No definitive conclusions can be drawn regarding M1 spatial representation, reactivity, or glucose metabolism in CRPS. There is limited evidence for bilateralM1 disinhibition in CRPS of the upper limb. Perspective: Despite widely held assumptions of primary motor cortex dysfunction in complex regional pain syndrome, there is only evidence to support bilateral disinhibition, and there is high risk of bias across the literature. Refereed/Peer-reviewed

That complex regional pain syndrome (CRPS) is associated with functional reorganization in the primary somatosensory cortex (S1) is widely accepted and seldom questioned. Despite more than a decade of research, there has been no systematic review of the CRPS literature concerning the changes in S1 function, and therefore the extent of these changes is unclear. Here we conduct a systematic review and meta-analysis to quantify the spatial and temporal aspects of S1 function in CRPS. A comprehensive search strategy identified functional neuroimaging studies of S1 in CRPS. We adhered to a rigorous systematic review protocol when extracting data and appraising risk of bias. Outcomes were grouped into spatial representation; activation levels, including disinhibition; peak latency of activation; and glucose metabolism. Meta-analysis was conducted where possible. Fifteen studies were included, all investigating upper-extremity CRPS. In patients with CRPS, the S1 spatial representation of the affected hand is smaller than that of the unaffected hand and that of non-CRPS controls; however, this evidence comes from only a few studies. There is no difference in activation, disinhibition, or latency of peripherally evoked S1 responses in CRPS. The risk of bias was high across studies, mainly from unclear sampling methods and unblinded analysis of outcomes. Perspective: The evidence for a difference in function of the primary somatosensory cortex in CRPS compared with controls is clouded by high risk of bias and conflicting results, but reduced representation size seems consistent. Refereed/Peer-reviewed

Objective: Chronic pain is a common problem that is associated with mood disorders such as depression. The Depression, Anxiety, and Stress Scales (DASS-21) questionnaire is commonly used to help measure disordered mood. In this study, we used Rasch analysis to analyze the clinimetric properties of the DASS-21 in a chronic low back pain sample. Study Design and Setting: A Rasch analysis was conducted on data collected as a part of a randomized hospital-based placebo controlled trial. DASS-21 questionnaires were completed by the 154 enrolled participants. Results: The DASS-21 subscales fit the Rasch model. No differential item functioning was detected for age, gender, pain severity, or disability. Reliability for individual use was supported for the depression subscale (Person Separation Index [PSI]50.86) but group use only for the anxiety (PSI50.74) and stress (PSI50.82) subscales. A DASS-21 aggregate score of ‘‘negative affect’’ lacked fit to the Rasch model (c25191.48, P!0.001). Conclusion: This is the first study that used Rasch analysis to demonstrate that the DASS-21 subscales demonstrate adequate measurement properties for research involving groups with chronic pain. Only the DASS-21 depression subscale demonstrated adequate reliability for use with individuals with chronic pain. The use of a single DASS-21 aggregate score as a measure of ‘‘negative affect’’ was not supported. Refereed/Peer-reviewed

Background and Purpose Orofacial pain disorders are relatively uncommon and pose a substantial diagnostic challenge. This case report documents the diagnosis and management of hemifacial pain in a patient who was referred to an interdisciplinary pain medicine unit. The purpose of this case report is twofold. First, it presents complex regional pain syndrome (CRPS) as a potential differential diagnosis in cases of facial pain. Second, it describes the successful adaption of contemporary management approaches for distal-extremity CRPS to treat people with CRPS of the facial region. Case Description The patient had hemifacial pain and concomitant motor and autonomic symptoms after a small laceration of the eyelid. Extensive specialist medical evaluations were undertaken to exclude an underlying structural pathology. After detailed clinical assessments by a physical therapist, pain physician, and clinical psychologist, a diagnosis of CRPS involving the face was made. Outcomes The patient's pain was largely unresponsive to pharmacological agents. A modified graded motor imagery program, together with desensitization and discrimination training, was commenced by the physical therapist and clinical psychologist. A positive clinical response was indicated by a decrease in allodynia, normalization of motor control, and regained function in activities of daily living. Discussion Complex regional pain syndrome is an infrequently reported differential diagnosis that can be considered in patients with persistent facial pain. This case report highlights how careful examination and clinical decision making led to the use of an innovative therapeutic strategy to manage a challenging condition.

Editors' Note: Parkitny and O'Connell point out the divergence in the initial hypothesis and final article on repetitive transcranial magnetic stimulation for fibromyalgia and critique how the authors interpreted the study results. Guedj and Boyer, authors of the study, respond. Freeman makes interesting observations and raises questions regarding the higher rate of intensive care unit admission and mortality in patients with multiple sclerosis. Marrie and Garland offer additional clarification. —Chafic Karam, MD, and Robert C. Griggs, MD Boyer et al.1 diverge—without disclosure—from the registered protocol for this trial. The authors stated that …

Objective. To assess the effects of preclinic group education sessions and system redesign on tertiary pain medicine units and patient outcomes. Design. Prospective cohort study. Setting. Two public hospital multidisciplinary pain medicine units. Patients. People with persistent pain. Interventions. A system redesign from a “traditional” model (initial individual medical appointments) to a model that delivers group education sessions prior to individual appointments. Based on Patient Triage Questionnaires patients were scheduled to attend Self-Training Educative Pain Sessions (STEPS), a two day eight hour group education program, followed by optional patient-initiated clinic appointments. Outcome Measures. Number of patients completing STEPS who subsequently requested individual outpatient clinic appointment(s); wait-times; unit cost per new patient referred; recurrent health care utilization; patient satisfaction; Global Perceived Impression of Change (GPIC); and utilized pain management strategies. Results. Following STEPS 48% of attendees requested individual outpatient appointments. Wait times reduced from 105.6 to 16.1 weeks at one pain unit and 37.3 to 15.2 weeks at the second. Unit cost per new patient appointed reduced from $1,805 Australian Dollars (AUD) to AUD$541 (for STEPS). At 3 months, patients scored their satisfaction with “the treatment received for their pain” more positively than at baseline (change score = 0.88; P = 0.0003), GPIC improved (change score = 0.46; P < 0.0001) and mean number of active strategies utilized increased by 4.12 per patient ( P = 0.0004). Conclusions. The introduction of STEPS was associated with reduced wait-times and costs at public pain medicine units and increased both the use of active pain management strategies and patient satisfaction.

Many chronic pain and psychiatric conditions are associated with changes in the concentrations of cytokines. Cytokine concentrations may also be associated with pain and mood during early recovery after injury. We aimed to investigate this in people after acute orthopaedic trauma. We tested 240 randomly selected serum samples obtained from a cohort of patients enrolled in a larger project investigating recovery following wrist fractures. Patients (18–75 years old) were prospectively recruited from three tertiary hospital outpatient clinics in Sydney, Australia. All participants were interviewed and completed validated questionnaires; 78% of participants also consented to a blood test. Serum cytokine concentrations were measured using a human 25-plex panel and luminex technology. In the primary analysis, regression models investigated the relationship between a priori -nominated cytokines and pain, depression, anxiety, stress, and quality of sleep. Pain was positively associated with increased systemic concentrations of CCL5 ( r = 0.25 p r = 0.25 p r = 0.22 p r = 0.22 p r = 0.19 p