Natural neural projection dynamics underlying social behavior.

Social interaction is a complex behavior essential for many species and is impaired in major neuropsychiatric disorders. Pharmacological studies have implicated certain neurotransmitter systems in social behavior, but circuit-level understanding of endogenous neural activity during social interaction is lacking. We therefore developed and applied a new methodology, termed fiber photometry, to optically record natural neural activity in genetically and connectivity-defined projections to elucidate the real-time role of specified pathways in mammalian behavior. Fiber photometry revealed that activity dynamics of a ventral tegmental area (VTA)-to-nucleus accumbens (NAc) projection could encode and predict key features of social, but not novel object, interaction. Consistent with this observation, optogenetic control of cells specifically contributing to this projection was sufficient to modulate social behavior, which was mediated by type 1 dopamine receptor signaling downstream in the NAc. Direct observation of deep projection-specific activity in this way captures a fundamental and previously inaccessible dimension of mammalian circuit dynamics.

Specialized coding of sensory, motor and cognitive variables in VTA dopamine neurons.

There is increased appreciation that dopamine neurons in the midbrain respond not only to reward1 and reward-predicting cues1,2, but also to other variables such as the distance to reward3, movements4-9 and behavioural choices10,11. An important question is how the responses to these diverse variables are organized across the population of dopamine neurons. Whether individual dopamine neurons multiplex several variables, or whether there are subsets of neurons that are specialized in encoding specific behavioural variables remains unclear. This fundamental question has been difficult to resolve because recordings from large populations of individual dopamine neurons have not been performed in a behavioural task with sufficient complexity to examine these diverse variables simultaneously. Here, to address this gap, we used two-photon calcium imaging through an implanted lens to record the activity of more than 300 dopamine neurons from the ventral tegmental area of the mouse midbrain during a complex decision-making task. As mice navigated in a virtual-reality environment, dopamine neurons encoded an array of sensory, motor and cognitive variables. These responses were functionally clustered, such that subpopulations of neurons transmitted information about a subset of behavioural variables, in addition to encoding reward. These functional clusters were spatially organized, with neighbouring neurons more likely to be part of the same cluster. Together with the topography between dopamine neurons and their projections, this specialization and anatomical organization may aid downstream circuits in correctly interpreting the wide range of signals transmitted by dopamine neurons.

Literature review on the use of methoxyflurane in the management of pain in cancer-related procedures.

INTRODUCTION: Self-administered methoxyflurane, also known as Penthrox, at a sub-anesthetic dose is a short-term, fast-acting, and safe analgesic that may provide suitable pain relief for cancer patients. This review aims to compile the existing evidence on methoxyflurane and its efficacy in reducing pain during cancer-related procedures. METHODS: A literature search was conducted through OVID Medline and Embase. The search was limited to articles published between 2012 and 2021 and studies were included if they assessed the efficacy of methoxyflurane to reduce pain in cancer-related procedures. All types of cancer were included. RESULTS: The literature search yielded seven studies published between 2012 and 2021. The studies analyzed assessed methoxyflurane use in prostate biopsy, colonoscopy, removal of brachytherapy rods, and bone marrow biopsy. Various research designs were employed, including three randomized controlled trials, two prospective observational studies, one retrospective, and one non-randomized controlled trial. In all, methoxyflurane has a demonstrated ability to reduce pain in these procedures. CONCLUSION: In the limited studies available in evaluating the efficacy of methoxyflurane for reducing procedural pain during cancer-related procedures, all have demonstrated clinical equivalency or superiority. Pain relief appears to be equivalent however methoxyflurane overcomes the standard limitations of respiratory sedation and has demonstrated quicker procedural recovery times than traditional sedation methods. The accumulated data to date supports the use of methoxyflurane which can supplement or supplant current methods of analgesia in cancer-related procedures.

Quality of life issues in patients with bone metastases: A systematic review.

INTRODUCTION: Bones are frequent sites of metastatic disease, observed in 30-75% of advanced cancer patients. Quality of life (QoL) is an important endpoint in studies evaluating the treatments of bone metastases (BM), and many patient-reported outcome tools are available. The primary objective of this systematic review was to compile a list of QoL issues relevant to BM and its interventions. The secondary objective was to identify common tools used to assess QoL in patients with BM, and the QoL issues they fail to address. METHODS: A search was conducted on Ovid MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases between 1946 and 27 January 2023 with the keywords "bone metastases", "quality of life", and "patient reported outcomes". Specific QoL issues in original research studies and the QoL tools used were extracted. RESULTS: The review identified the QoL issues most prevalent to BM in the literature. Physical and functional issues observed in patients included pain, interference with ambulation and daily activities, and fatigue. Psychological symptoms, such as helplessness, depression, and anxiety were also common. These issues interfered with patients' relationships and social activities. Items not mentioned in existing QoL tools were related to newer treatments of BM, such as pain flare, flu-like symptoms, and jaw pain due to osteonecrosis. CONCLUSIONS: This systematic review highlights that QoL issues for patients with BM have expanded over time due to advances in BM-directed treatments. If they are relevant, additional treatment-related QoL issues identified need to be validated prospectively by patients and added to current assessment tools.

Comparison of major spine navigation platforms based on key performance metrics: a meta-analysis of 16,040 screws.

PURPOSE: The objective of this meta-analysis is to compare available computer-assisted navigation platforms by key performance metrics including pedicle screw placement accuracy, operative time, neurological complications, and blood loss. METHODS: A systematic review was conducted using major databases for articles comparing pedicle screw accuracy of computer-assisted navigation to conventional (freehand or fluoroscopy) controls via post-operative computed tomography. Outcome data were extracted and pooled by random-effects model for analysis. RESULTS: All navigation platforms demonstrated significant reduction in risk of breach, with Stryker demonstrating the highest accuracy compared to controls (OR 0.16 95% CI 0.06 to 0.41, P < 0.00001, I2 = 0%) followed by Medtronic. There were no significant differences in accuracy or most surgical outcome measures between platforms; however, BrainLab demonstrated significantly faster operative time compared to Medtronic by 30 min (95% CI - 63.27 to - 2.47, P = 0.03, I2 = 74%). Together, there was significantly lower risk of major breach in the navigation group compared to controls (OR 0.42, 95% CI 0.27-0.63, P < 0.0001, I2 = 56%). CONCLUSIONS: When comparing between platforms, Stryker demonstrated the highest accuracy, and Brainlab the shortest operative time, both followed by Medtronic. No significant difference was found between platforms regarding neurologic complications or blood loss. Overall, our results demonstrated a 60% reduction in risk of major breach utilizing computer-assisted navigation, coinciding with previous studies, and supporting its validity. This study is the first to directly compare available navigation platforms offering insight for further investigation and aiding in the institutional procurement of platforms. LEVEL 3 EVIDENCE: Meta-analysis of Level 3 studies.

Predictors of hospital-acquired pressure injuries in patients with complete spinal cord injury: a retrospective case-control study.

BACKGROUND: Despite current best practices, pressure injuries (PI) remain a devastating and prevalent hospital-acquired complication for patients with acute traumatic spinal cord injuries (SCIs). This study examined associations between risk factors for PI development in patients with complete SCI, such as norepinephrine dose and duration, and other demographic factors or lesion characteristics. METHODS: This case-control study included adults with acute complete SCIs ASIA-A, who were admitted to a level-one trauma center between 2014-18. A retrospective review was implement using data on patient and injury characteristics, including age, gender, level of SCI (cervical vs. thoracic), Injury Severity Score (ISS), length of stay (LOS) and mortality; presence/absence of PI during their acute hospital stay; and treatment factors such as spinal surgery, mean arterial pressure (MAP) targets, and vasopressor treatment. Multivariable logistic regression evaluated associations with PI. RESULTS: Eighty-two out of 103 eligible patients had complete data, and 30 (37%) developed PIs. Patient and injury characteristics, including age (Mean: 50.6; SD:21.3), location of SCI (48 cervical, 59%) and ISS (Mean 33.1; SD:11.8), did not differ between PI and non-PI groups. Logistic regression analysis revealed that male gender (OR:34.1; CI95:2.3-506.5, p = 0.010) and increased LOS (log-transformed; OR:20.5, CI95:2.8-149.9, p = 0.003) were associated with increased risk of PI. Having an order for a MAP > 80mmg (OR:0.05; CI95:0.01-0.30, p = 0.001) was associated with a reduced risk of PI. There were no significant associations between PI and duration of norepinephrine treatment. CONCLUSIONS: Norepinephrine treatment parameters were not associated with development of PI, suggesting that MAP targets should be a focus for future investigations for SCI management. Increasing LOS should highlight the need for high-risk PI prevention and vigilance.

Prediabetes and insulin resistance are associated with lower trabecular bone score (TBS): cross-sectional results from the Study of Women's Health Across the Nation TBS Study.

In pre- and early perimenopausal women, prediabetes (with blood glucose ≥ 110 mg/dL) and greater insulin resistance are associated with worse trabecular bone quality (as assessed by trabecular bone score). PURPOSE: Diabetes mellitus (DM) is associated with lower trabecular bone score (TBS) and fracture; less certain is whether the precursor states of prediabetes and increased insulin resistance are also related to adverse bone outcomes. We examined, in women who do not have DM, the associations of glycemic status (prediabetes vs. normal) and insulin resistance with TBS. METHODS: This was a cross-sectional analysis of baseline data collected from 42- to 52-year-old, pre- and perimenopausal participants in the Study of Women's Health Across the Nation (SWAN) TBS Study. Women with prediabetes were categorized as having either high prediabetes if their fasting glucose was between 110 and 125 mg/dL or low prediabetes if their fasting glucose was between 100 and 109 mg/dL. Normoglycemia was defined as a fasting glucose below 100 mg/dL. RESULTS: In multivariable linear regression, adjusted for age, race/ethnicity, menopause transition stage, cigarette use, calcium and vitamin D supplementation, lumbar spine bone mineral density, and study site, women with high prediabetes had 0.21 (p < 0.0001) standard deviations (SD) lower TBS than those with normoglycemia. Low prediabetes was not associated with lower TBS. When HOMA-IR levels were ≥ 1.62, each doubling of HOMA-IR was associated with a 0.11 SD decrement in TBS (p = 0.0001). CONCLUSION: Similar to diabetics, high prediabetics have lower TBS than normoglycemic individuals. Women with greater insulin resistance have lower TBS even in the absence of DM. Future studies should examine the associations of high prediabetes and insulin resistance with incident fracture.

The efficacy of primary sacroiliac joint fusion for low back pain caused by sacroiliac joint pathology: a systematic review and meta-analysis.

PURPOSE: Conduct a systematic review to quantify the effect of primary sacroiliac joint fusion (SIJF) for the treatment of sacroiliac (SI) joint pathology on patient reported outcomes. METHODS: Medline, Embase, Cochrane, PubMed, and Scopus databases were searched prior to August 18th, 2020 for all English-Language studies involving the treatment of SIJ pathology through SIJF and/or conservative management (CM). The quality of included studies was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Primary outcome measure was the Visual Analogue Scale (VAS) for low back pain. Secondary outcome measure was the Oswestry Disability Index (ODI) and the incidence of adverse reactions. RESULTS: A total of 564 patients and six studies were included. The overall quality of evidence analyzed by this review was low (GRADE = 0). Five out of the six studies were industry funded. The VAS standardized mean difference (SMD) between SIJF and CM at three months and six months follow-up was - 1.4 [95% confidence interval - 2.3, - 0.6] and - 1.5 [95% CI - 1.8, - 1.1]. The ODI SMD between SIJF and CM scores at three months and 6 months follow-up was - 0.9 [95% CI - 1.1, - 0.7] and - 1.1 [95% CI - 1.6, - 0.5]. The odds ratio of adverse reactions due to SIJF compared to CM was 1.9 [95% CI 0.1, 42.8]. CONCLUSION: Based on the limited number of independent trials with long-term follow-up, SIJF shows potential as a surgical treatment option for SIJ pathology. PROSPERO REGISTRATION: CRD42020206149 (25th September 2020).

Validation of the Subgroups for Targeted Treatment for Back (STarT Back) screening tool at a tertiary care centre.

BACKGROUND: The Subgroups for Targeted Treatment for Back (STarT Back) tool is a screening questionnaire developed to identify modifiable risk factors for back pain disability in primary care. Given the ability of this tool to assist with early identification of patients at high risk, we examined its concurrent convergent and known-group construct validity in tertiary care. METHODS: This was a case-control study of adult (age > 18 yr) patients with and without an active work-related compensation claim recruited from an academic health centre between August 2017 and May 2019. Patients in the study group were assessed by a physiotherapist and an orthopedic surgeon in a spine specialty program designed to assess and treat workplace injuries. The control group included patients referred to an orthopedic spine surgeon in a publicly funded specialty clinic where an advanced practice physiotherapist determined the need for surgical consultation. We used the Roland-Morris Disability Questionnaire (RMDQ) and the Hospital Anxiety and Depression Scale (HADS) to determine the convergent and known-group construct validity of the STarT Back tool. RESULTS: Fifty case and 50 control participants were included. We observed moderate to high association between the STarT Back total score, psychosocial subscore and risk categories and the RMDQ and HADS scores in the expected direction (p < 0.001). A significant association was observed between risk group allocation and depression (area under the curve values > 80), having a compensable injury and work status (p = 0.002-0.001). CONCLUSION: The STarT Back tool was able to differentiate between patients with and without a compensable injury and patients with different levels of work status. The tool has acceptable convergent and known-group construct validity and can assist in clinical decision-making in a tertiary care setting where adjunct psychologic management may be indicated.

Survival after surgery for spinal metastases: a population-based study.

BACKGROUND: There are limited published data on population estimates of survival after spinal surgery for metastatic disease. We performed a population-based study to evaluate survival and complications among patients with cancer who underwent surgery for spinal metastases in Ontario, Canada, between 2006 and 2016. METHODS: We used health administrative databases to identify all patients who underwent surgery for spinal metastases in Ontario between Jan. 1, 2006, and Dec. 31, 2016. We assessed overall survival, mortality rates according to primary cancer lesion and complications after surgery. We contrast the results to those for a comparable cohort from 1991 to 1998. RESULTS: A total of 2646 patients (1194 women [45.1%]; mean age 62.5 yr [standard deviation 12.2 yr]) were identified. The median survival time was 236 (interquartile range 84-740) days. Mortality was highest for patients with melanoma, upper gastrointestinal cancer and lung cancer, with 50% dying within 90 days of surgery. The longest median survival times were observed for primary cancers of the thyroid (906 d) and breast (644 d), and myeloma (830 d). Overall 90-day and 1-year mortality rates were 29% and 59%, respectively. CONCLUSION: We identified differential survivorship based on primary tumour type and a shift in the distribution of operations performed for specific primary cancers over the past 2 decades in Ontario. Overall reductions in mortality associated with this shift in treatment may reflect the use of adjuvant therapies and more personalized treatment approaches.

"Looking Under the Hood" of Anchor-Based Assessment of Clinically Important Change: A Machine Learning Approach.

OBJECTIVES: The Global Assessment of Change (GAC) item has facilitated the interpretation of change in patient-reported outcomes, providing an anchor for computing minimally important differences. Construct validity has been documented via disease-specific patient-reported outcomes change. We examined what domains, sociodemographic characteristics, attributions of change, and cognitive-appraisal processes are reflected in GAC ratings. METHODS: This secondary analysis examined data from 1,481 chronically ill patients and caregivers surveyed at baseline and 17 months. Items queried change since baseline in overall disease symptoms (GAC) and in physical, emotional, and social functioning. Candidate predictors included sociodemographic factors, health-related quality-of-life domains, change attributions, and quality-of-life appraisal processes. Least absolute shrinkage and selection operator and bootstrapping tested 77 predictors' effectiveness and stability. RESULTS: GAC worsening was notably associated with being disabled (ß = -0.24) and having difficulty paying bills (ß = -0.13). GAC was better explained by the physical domain than the emotional or social (ß = 0.67, 0.10, and 0.03, respectively; R2adj = 0.63) after sociodemographic-covariate adjustment. In a separate model (R2adj = 0.18), GAC variance was explained by attributions about changing health and changing response of one's health team, goals related to solving healthcare problems and maintaining activities, and appraisal about things getting better (ß = -0.14, 0.08, -0.07, 0.05, 0.21, respectively; prange ~0.0005-0.05) after adjustment. CONCLUSIONS: The GAC primarily reflects the physical domain, and the GAC reflects attributions, goals, and patterns of emphasis related to change in health and healthcare. Commonly unmeasured factors have some bearing on GAC scores and can facilitate the interpretation of change.

Basomedial amygdala mediates top-down control of anxiety and fear.

Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.

Patient Factors That Matter in Predicting Hip Arthroplasty Outcomes: A Machine-Learning Approach.

BACKGROUND: Despite the success of total hip arthroplasty (THA), approximately 10%-15% of patients will be dissatisfied with their outcome. Identifying patients at risk of not achieving meaningful gains postoperatively is critical to pre-surgical counseling and clinical decision support. Machine learning has shown promise in creating predictive models. This study used a machine-learning model to identify patient-specific variables that predict the postoperative functional outcome in THA. METHODS: A prospective longitudinal cohort of 160 consecutive patients undergoing total hip replacement for the treatment of degenerative arthritis completed self-reported measures preoperatively and at 3 months postoperatively. Using four types of independent variables (patient demographics, patient-reported health, cognitive appraisal processes and surgical approach), a machine-learning model utilizing Least Absolute Shrinkage Selection Operator (LASSO) was constructed to predict postoperative Hip Disability and Osteoarthritis Outcome Score (HOOS) at 3 months. RESULTS: The most predictive independent variables of postoperative HOOS were cognitive appraisal processes. Variables that predicted a worse HOOS consisted of frequent thoughts of work (ß = -0.34), frequent comparison to healthier peers (ß = -0.26), increased body mass index (ß = -0.17), increased medical comorbidities (ß = -0.19), and the anterior surgical approach (ß = -0.15). Variables that predicted a better HOOS consisted of employment at the time of surgery (ß = 0.17), and thoughts related to family interaction (ß = 0.12), trying not to complain (ß = 0.13), and helping others (ß = 0.22). CONCLUSIONS: This clinical prediction model in THA revealed that the factors most predictive of outcome were cognitive appraisal processes, demonstrating their importance to outcome-based research. LEVEL OF EVIDENCE: Prognostic Level 1.

Moving toward better health: exercise practice is associated with improved outcomes after spine surgery in people with degenerative lumbar conditions.

Background: Recovery and rehabilitation following surgery can take many months. Understanding what patients can do to facilitate recovery would be beneficial for spinal surgeons. This study sought to evaluate the impact of exercise practice, before and after surgery, on long-term outcomes of spine surgery in a robust clinical sample. Methods: This prospective longitudinal cohort study included adult patients undergoing spinal surgery for degenerative spinal conditions. Patients were administered a survey that included preoperative and postoperative exercise practices and the following patient-reported outcome measures: the physical component score (PCS) and mental component score (MCS) of the Medical Outcomes Study 36-Item Short Form Survey (Rand-36), the Oswestry Disability Index (ODI) score, the Numeric Rating Scale (NRS) score for pain and the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Short Form score. Random effects models investigated the relationship of exercise, follow-up time and their interaction in predicting each patient-reported outcome measure over time, with and without sociodemographic covariates. Results: There were 168 patients in the study sample with up to 12 months of follow-up data. Analysis revealed modest significant main effects of exercise on PCS, MCS, ODI and PROMIS scores and main effects of time on all outcomes. The exercise-by-time interaction was significant in predicting the trajectories of the ODI and MCS scores. When full models were adjusted for education and employment status, interaction effects were no longer significant, but exercise main effects remained significant for ODI score. Conclusion: Patients who engage in exercise before and after spine surgery have better mental health and spine-specific recovery trajectories than those who do not. All health care providers should encourage patients to exercise while they are waiting for surgery within preoperative limitations and as soon as they are able after surgery and to continue this over the long term.

Contexte: Le rétablissement et la réadaptation postopératoires s'échelonnent parfois sur plusieurs mois. Comprendre ce que les patients peuvent faire pour faciliter leur rétablissement serait utile aux spécialistes de la chirurgie de la colonne vertébrale. Cette étude a voulu évaluer l'impact de la pratique d'exercices avant et après une chirurgie de la colonne vertébrale sur son issue à long terme dans un solide échantillon clinique. Méthodes: Cette étude de cohorte longitudinale prospective a regroupé des patients adultes qui devaient subir une chirurgie de la colonne vertébrale pour des maladies dégénératives. Les patients ont été invités à répondre à un questionnaire qui portait entre autre sur la pratique d'exercices pré- et postopératoires et sur les paramètres autorapportés suivants : scores aux composantes physique (PCS) et mentale (MCS) du questionnaire SF-36 (Medical Outcomes Study 36-Item Short Form Survey [Rand-36]), à l'échelle d'incapacité d'Oswestry (ODI), à une échelle d'évaluation numérique (ÉÉN) de la douleur et au questionnaire court PROMIS (Patient-Reported Outcome Measurement Information System) sur l'interférence de la douleur. Des modèles à effets aléatoires ont permis d'analyser les liens entre l'exercice, la durée du suivi et leur interaction pour ce qui est de prédire chacun des paramètres autorapportés au fil du temps, avec et sans les covariables sociodémographiques. Résultats: L'étude a regroupé 168 patients et les données pour un suivi allant jusqu'à 12 mois. L'analyse a fait état d'effets majeurs significatifs modestes de l'exercice sur les paramètres PCS, MCS, ODI et PROMIS et d'effets majeurs du temps sur tous les paramètres. L'interaction entre exercices et durée du suivi a été significative pour prédire la trajectoire des scores ODI et MCS. Lorsque les modèles intégraux ont été ajustés pour tenir compte du niveau de scolarité et du statut professionnel, les effets de l'interaction n'étaient plus significatifs, mais les effets majeurs de l'exercice sont demeurés significatifs pour le score ODI. Conclusion: Les patients qui ont fait des exercices avant et après une chirurgie de la colonne vertébrale ont présenté des trajectoires plus favorables au plan de la santé mentale et du rétablissement de leur colonne vertébrale comparativement à ceux qui n'avaient pas fait d'exercices. Tous les professionnels de la santé devraient encourager les patients à faire des exercices pendant qu'ils attendent leur chirurgie en tenant compte de leurs limites préopératoires, à les reprendre le plus rapidement possible après la chirurgie et à les maintenir à long terme.

Temporal increases in 25-hydroxyvitamin D in midlife women: Longitudinal results from the Study of Women's Health Across the Nation.

OBJECTIVE: 25-hydroxyvitamin D (25(OH)D) is critical for bone mineralization and may prevent fractures. Understanding vitamin D deficiency trends in midlife women is particularly important given their concurrent menopausal changes that increase risk for fracture. We aimed to evaluate changes in mean 25(OH)D over time and their determinants in a racially, ethnically and socioeconomically diverse cohort of midlife women. DESIGN: A multi-centre prospective cohort study. PATIENTS: 1585 women ages 42-52 years at baseline. MEASUREMENTS: We measured serum 25(OH)D at 2 time points (1998-2000 and 2009-2011). Between-visit change was assessed in the whole cohort and in socioeconomic and demographic subgroups. Among those with vitamin D deficiency (25(OH)D <30 nmol/L) at baseline, we evaluated determinants of persistent deficiency at follow-up. RESULTS: Mean 25(OH)D increased from 53.8 to 70.0 nmol/L (P < 0.001), and the prevalence of deficiency decreased from 20.4% to 9.7% (P < 0.001). While baseline 25(OH)D differed among subgroups, the changes in 25(OH)D were similar among groups. The proportion of women reporting dietary supplement use increased from 40.8% to 67.1% (P < 0.001), and the increase in 25(OH)D was significantly higher in supplement users. Among women with vitamin D deficiency at baseline, White women and supplement users were less likely to remain deficient at follow-up. CONCLUSIONS: Among midlife women, temporal increases in 25(OH)D concentrations are driven largely by increases in supplement use. The proportion of women with 25(OH)D <30 nmol/L and thus at high risk for skeletal consequences remains substantial. Targeted screening for vitamin D deficiency in populations at risk for fragility fracture may be advisable.

Dopamine neurons modulate neural encoding and expression of depression-related behaviour.

Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.

Predictive factors of survival in a surgical series of metastatic epidural spinal cord compression and complete external validation of 8 multivariate models of survival in a prospective North American multicenter study.

BACKGROUND: This study was designed to identify preoperative predictors of survival in surgically treated patients with metastatic epidural spinal cord compression (MESCC), to examine how these predictors are related to 8 prognostic models, and to perform the first full external validation of these models in accordance with the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement. METHODS: One hundred forty-two surgically treated patients with MESCC were enrolled in a prospective, multicenter North American cohort study and were followed for 12 months or until death. Cox regression was used. Noncollinear predictors with < 10% missing data, with ≥ 10 events per stratum, and with P < .05 in a univariate analysis were tested through a backward stepwise selection. For the original and revised Tokuhashi prognostic scoring systems (PSSs), Tomita PSS, modified Bauer PSS, van der Linden PSS, Bartels model, Oswestry Spinal Risk Index, and Bollen PSS, this study examined calibration graphically, discrimination with Harrell c-statistics, and survival stratified by risk groups with the Kaplan-Meier method and log-rank test. RESULTS: The following were significant in the univariate analysis: type of primary tumor, sex, organ metastasis, body mass index, preoperative radiotherapy to MESCC, physical component (PC) of the 36-Item Short Form Health Survey, version 2 (SF-36v2), and EuroQol 5-Dimension (EQ-5D) Questionnaire. Breast, prostate and thyroid primary tumor (HR: 2.9; P =.0005), presence of organ metastasis (hazard ratio (HR): 2.0; P = .005) and SF-36v2 PC (HR: 0.95; P < .0001) were associated with survival in multivariable analysis. Predicted prognoses poorly matched observed values on calibration plots; Bartels model calibration slope was 0.45. Bollen PSS (0.61; 95% CI: 0.58-0.64) and Bartels model (0.68; 95% CI: 0.65-0.71) had the lowest and highest c-statistics, respectively. CONCLUSIONS: The primary tumor type (breast, prostate, or thyroid), an absence of organ metastasis, and a lower degree of physical disability are preoperative predictors of longer survival for surgical MESCC patients. These results are in keeping with current models. This full external validation of 8 prognostic PSSs or model of survival in surgical MESCC patients has revealed that calibration is poor, especially for long-term survivors, whereas discrimination is possibly helpful.

Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial.

BACKGROUND: Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. METHODS: This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of -2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 µg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. FINDINGS: Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the romosozumab group and -0·6% (-1·0 to -0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p<0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. INTERPRETATION: Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture. FUNDING: Amgen, Astellas, and UCB Pharma.

Quality of Life and Adaptation in People With Spinal Cord Injury: Response Shift Effects From 1 to 5 Years Postinjury.

OBJECTIVE: To investigate response shift effects in spinal cord injury (SCI) over 5 years postinjury. DESIGN: Prospective cohort study observed at 1, 2, and 5 years post-SCI. SETTING: Specialized SCI centers. PARTICIPANTS: Sample included 1125, 760, and 219 participants at 1, 2, and 5 years post-SCI (N = 2104). The study sample was 79% men; 39% were motor/sensory complete (mean age, 44.6±18.3y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patient-reported outcomes included the Medical Outcomes Study 36-Item Short-Form Health Survey version 2 and the Life Satisfaction-11 Questionnaire. Participant latent variable scores were adjusted for (1) potential attrition bias and (2) propensity scores reflecting risk of worse outcomes. The Oort structural equation modeling approach for detecting and accounting for response shift effects was used to test the hypothesis that people with SCI would undergo response shifts over follow-up. RESULTS: The study data comprised the time after FIM scores, an objective measure of motor and cognitive function, had improved and stabilized. Three latent variables (Physical, Mental, and Symptoms) were modeled over time. The response shift model indicated uniform recalibration and reconceptualization response shift effects over time. When adjusted for these response shift effects, Physical showed small true change improvements at 2- and 5-year follow-up, despite FIM stability. CONCLUSIONS: We detected recalibration and reconceptualization response shift effects in 1- to 5-year follow-up of people with SCI. Despite stable motor and cognitive function, people with SCI are adapting to their condition. This adaptation reflects a progressive disconnection between symptoms and physical or mental health, and a real improvement in the Physical latent variable.

Health Conditions: Effect on Function, Health-Related Quality of Life, and Life Satisfaction After Traumatic Spinal Cord Injury. A Prospective Observational Registry Cohort Study.

OBJECTIVE: To analyze relations among injury, demographic, and environmental factors on function, health-related quality of life (HRQoL), and life satisfaction in individuals with traumatic spinal cord injury (SCI). DESIGN: Prospective observational registry cohort study. SETTING: Specialized acute and rehabilitation SCI centers. PARTICIPANTS: Participants (N=340) from the Rick Hansen Spinal Cord Injury Registry (RHSCIR) who were prospectively recruited from 2004 to 2014 were included. The model cohort participants were 79.1% men, with a mean age of 41.6±17.3 years. Of the participants, 34.7% were motor/sensory complete (ASIA Impairment Scale [AIS] grade A). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Path analysis was used to determine relations among SCI severity (AIS grade and anatomic level [cervical/thoracolumbar]), age at injury, education, number of health conditions, functional independence (FIM motor score), HRQoL (Medical Outcomes Study 36-Item Short-Form Health Survey [Version 2] Physical Component Score [PCS] and Mental Component Score [MCS]), and life satisfaction (Life Satisfaction-11 [LiSat-11]). Model fit was assessed using recommended published indices. RESULTS: Goodness of fit of the model was supported by all indices, indicating the model results closely matched the RHSCIR data. Higher age, higher severity injuries, cervical injuries, and more health conditions negatively affected FIM motor score, whereas employment had a positive effect. Higher age, less education, more severe injuries (AIS grades A-C), and more health conditions negatively correlated with PCS (worse physical health). More health conditions were negatively correlated with a lower MCS (worse mental health), however were positively associated with reduced function. Being married and having higher function positively affected Lisat-11, but more health conditions had a negative effect. CONCLUSIONS: Complex interactions and enduring effects of health conditions after SCI have a negative effect on function, HRQoL, and life satisfaction. Modeling relations among these types of concepts will inform clinicians how to positively effect outcomes after SCI (eg, development of screening tools and protocols for managing individuals with traumatic SCI who have multiple health conditions).