Targeted mapping and utilization of the perihepatic surface for therapeutic beta cell replacement and retrieval in diabetic non-human primates.

Introduction: Successful diabetes reversal using pancreatic islet transplantation by various groups illustrates the significant achievements made in cell-based diabetes therapy. While clinically, intraportal islet delivery is almost exclusively used, it is not without obstacles, including instant blood-mediated inflammatory reaction (IBMIR), relative hypoxia, and loss of function over time, therefore hindering long-term success. Here we demonstrate the perihepatic surface of non-human primates (NHPs) as a potential islet delivery site maximizing favorable characteristics, including proximity to a dense vascular network for adequate oxygenation while avoiding IBMIR exposure, maintenance of portal insulin delivery, and relative ease of accessibility through minimally invasive surgery or percutaneous means. In addition, we demonstrate a targeted mapping technique of the perihepatic surface, allowing for the testing of multiple experimental conditions, including a semi-synthetic hydrogel as a possible three-dimensional framework to improve islet viability. Methods: Perihepatic allo-islet cell transplants were performed in immunosuppressed cynomolgus macaques using a targeted mapping technique to test multiple conditions for biocompatibility. Transplant conditions included islets or carriers (including hydrogel, autologous plasma, and media) alone or in various combinations. Necropsy was performed at day 30, and histopathology was performed to assess biocompatibility, immune response, and islet viability. Subsequently, single-injection perihepatic allo-islet transplant was performed in immunosuppressed diabetic cynomolgus macaques. Metabolic assessments were measured frequently (i.e., blood glucose, insulin, C-peptide) until final graft retrieval for histopathology. Results: Targeted mapping biocompatibility studies demonstrated mild inflammatory changes with islet-plasma constructs; however, significant inflammatory cell infiltration and fibrosis were seen surrounding sites with the hydrogel carrier affecting islet viability. In diabetic NHPs, perihepatic islet transplant using an autologous plasma carrier demonstrated prolonged function up to 6 months with improvements in blood glucose, exogenous insulin requirements, and HbA1c. Histopathology of these islets was associated with mild peri-islet mononuclear cell infiltration without evidence of rejection. Discussion: The perihepatic surface serves as a viable site for islet cell transplantation demonstrating sustained islet function through 6 months. The targeted mapping approach allows for the testing of multiple conditions simultaneously to evaluate immune response to biomaterials at this site. Compared to traditional intraportal injection, the perihepatic site is a minimally invasive approach that allows the possibility for graft recovery and avoids IBMIR.

Characterization of pain-related behaviors in a rat model of acute-to-chronic low back pain: single vs. multi-level disc injury.

Introduction: Low back pain is the most common type of chronic pain. We examined pain-related behaviors across 18 weeks in rats that received injury to one or two lumbar intervertebral discs (IVD) to determine if multi-level disc injuries enhance/prolong pain. Methods: Twenty-three Sprague-Dawley adult female rats were used: 8 received disc puncture (DP) of one lumbar IVD (L5/6, DP-1); 8 received DP of two lumbar IVDs (L4/5 & L5/6, DP-2); 8 underwent sham surgery. Results: DP-2 rats showed local (low back) sensitivity to pressure at 6- and 12-weeks post-injury, and remote sensitivity to pressure (upper thighs) at 12- and 18-weeks and touch (hind paws) at 6, 12 and 18-weeks. DP-1 rats showed local and remote pressure sensitivity at 12-weeks only (and no tactile sensitivity), relative to Sham DP rats. Both DP groups showed reduced distance traveled during gait testing over multiple weeks, compared to pre-injury; only DP-2 rats showed reduced distance relative to Sham DP rats at 12-weeks. DP-2 rats displayed reduced positive interactions with a novel adult female rat at 3-weeks and hesitation and freezing during gait assays from 6-weeks onwards. At study end (18-weeks), radiological and histological analyses revealed reduced disc height and degeneration of punctured IVDs. Serum BDNF and TNFα levels were higher at 18-weeks in DP-2 rats, relative to Sham DP rats, and levels correlated positively with remote sensitivity in hind paws (tactile) and thighs (pressure). Discussion: Thus, multi-level disc injuries resulted in earlier, prolonged and greater discomfort locally and remotely, than single-level disc injury. BDNF and TNFα may have contributing roles.

Associations between empirically proportionate and disproportionate fears of cancer recurrence and anxiety and depression in uveal melanoma survivors: Five-year prospective study.

OBJECTIVE: Fear of cancer recurrence (FCR) may develop into elevated anxiety or depression symptoms, but few risk factors for this development are known. Objective recurrence risk estimation is possible in some cancers. Using theories of risk communication and phobias, we examined whether the proportionality of FCR to known objective recurrence risk influences the development of anxiety and depression symptoms. METHOD: Uveal melanoma (UM) patients can opt for reliable prognostic testing. Patients experience either a 'good' or 'poor' prognostic outcome, whereby 10-year mortality due to metastatic disease is, respectively, low or high. In a five-year prospective study of a consecutive sample of 589 UM survivors, we used random intercept cross lagged panel analyses to examine whether proportionality differentially influences whether FCR progresses to anxiety and depression. RESULTS: Positive cross paths predicting anxiety from FCR were stronger in the poor prognosis group than the good prognosis and not tested groups. Prognostic group differences were not evident for depression. CONCLUSIONS: FCR was more likely to progress to elevated anxiety symptoms when proportionate to the known objective recurrence risk. Objective evidence may play a prominent role in the development and structure of fear because it assumes a high epistemic weight that activates a wide range of emotional and cognitive responses. Interventions that assist survivors to tolerate FCR in the presence of higher recurrence risks may be important in reducing anxiety symptoms.

A bioengineered artificial interstitium supports long-term islet xenograft survival in nonhuman primates without immunosuppression.

Cell-based therapies hold promise for many chronic conditions; however, the continued need for immunosuppression along with challenges in replacing cells to improve durability or retrieving cells for safety are major obstacles. We subcutaneously implanted a device engineered to exploit the innate transcapillary hydrostatic and colloid osmotic pressure generating ultrafiltrate to mimic interstitium. Long-term stable accumulation of ultrafiltrate was achieved in both rodents and nonhuman primates (NHPs) that was chemically similar to serum and achieved capillary blood oxygen concentration. The majority of adult pig islet grafts transplanted in non-immunosuppressed NHPs resulted in xenograft survival >100 days. Stable cytokine levels, normal neutrophil to lymphocyte ratio, and a lack of immune cell infiltration demonstrated successful immunoprotection and averted typical systemic changes related to xenograft transplant, especially inflammation. This approach eliminates the need for immunosuppression and permits percutaneous access for loading, reloading, biopsy, and recovery to de-risk the use of "unlimited" xenogeneic cell sources to realize widespread clinical translation of cell-based therapies.

Prevalence, temporal course and risk factors for phantom eye symptoms in uveal melanoma.

BACKGROUND: Phantom eye symptoms (PES), particularly phantom visual sensations (PVS) and phantom eye pain (PEP), are common in enucleated patients and can lead to psychological distress. Current cross-sectional studies cannot examine the temporal course of symptoms, nor can they identify dynamic risk factors or consequences of PES. METHODS: Cohort study of 105 enucleated uveal melanoma patients returning self-report questionnaires, within 4 weeks of diagnosis and 6-, 12- and 24-months post-treatment. Questionnaires measuring PVS and PEP symptoms in the week prior to completion, pain severity, Hospital Anxiety and Depression Scale scores and the Functional Assessment of Cancer Therapy scale (FACT-G) measuring quality of life. RESULTS: PVS and PEP emerged after 6 months, were relatively stable over the study and did not remit. PVS showed 6-, 12- and 24-month prevalence rates of 44.6%, 48.2% and 30.2%, and PEP 16.1%, 18.4% and 17.5% respectively. PVS were generally elementary, with only 10-15% of the total cohort experiencing complex sensations. PEP was generally neither prolonged nor intense, except in a small proportion. PVS and PEP were showed moderate associations but did not predict each other prospectively. Anxiety within 4 weeks of diagnosis was a risk factor for the initiation of PEP. Neither PVS nor PEP prospectively predicted anxiety, depression or quality of life. CONCLUSIONS: PES were prevalent and non-remitting, beginning within 6 months of enucleation. PVS and PEP may not represent symptoms of a coherent syndrome. We discuss findings with reference to theories of phantom sensations, and directions for clinical practise and research.

Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats.

Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing human nucleus pulposus cells (NPCs), generated by certain conditions in degenerating discs, that was associated with the onset of discogenic back pain. Single-cell transcriptomic analysis of human tissues showed a strong correlation between a specific cell subtype and the pain condition associated with the human degenerated disc, suggesting that they are pain-triggering. The application of IVD degeneration-associated exogenous stimuli to healthy NPCs in vitro recreated a pain-associated phenotype. These stimulated NPCs activated functional human iPSC-derived sensory neuron responses in an in vitro organ-chip model. Injection of stimulated NPCs into the healthy rat IVD induced local inflammatory responses and increased cold sensitivity and mechanical hypersensitivity. Our findings reveal a previously uncharacterized pain-inducing mechanism mediated by NPCs in degenerating IVDs. These findings could aid in the development of NPC-targeted therapeutic strategies for the clinically unmet need to attenuate discogenic LBP.

Adverse childhood experience is associated with an increased risk of reporting chronic pain in adulthood: a stystematic review and meta-analysis.

Background: Adverse childhood experiences (ACEs) have been shown to negatively affect health in adulthood. Estimates of associations between ACEs and chronic painful conditions are lacking.Objectives: This systematic review and meta-analysis aimed to evaluate associations between exposure to ACEs and chronic pain and pain-related disability in adults.Methods: We searched 10 electronic databases from inception to February 2023. We included observational studies assessing associations between direct ACEs (childhood sexual, physical, emotional abuse, or neglect) alone or in combination with indirect ACEs (witnessing domestic violence, household mental illness), and adult chronic pain (≥3 months duration) and pain-related disability (daily activities limited by chronic pain). Pairs of reviewers independently extracted data and assessed study risks of bias. Random-effect models were used to calculate pooled adjusted odds ratios [aOR]. Tau square [T2], 95% prediction intervals [95%PI] and I2 expressed the amount of heterogeneity, and meta-regressions and subgroup meta-analyses investigated sources of heterogeneity (PROSPERO: CRD42020150230).Results: We identified 85 studies including 826,452 adults of which 57 studies were included in meta-analyses. Study quality was generally good or fair (n = 70). The odds of reporting chronic pain in adulthood were significantly higher among individuals exposed to a direct ACE (aOR, 1.45, 95%CI, 1.38-1.53). Individuals reporting childhood physical abuse were significantly more likely to report both chronic pain (aOR, 1.50, 95CI, 1.39-1.64) and pain-related disability (1.46, 95CI, 1.03-2.08) during adulthood. Exposure to any ACEs alone or combined with indirect ACEs significantly increase the odds of adult chronic painful conditions (aOR, 1.53, 95%CI, 1.42-1.65) and pain-related disability (aOR, 1.29; 95%CI, 1.01-1.66). The risk of chronic pain in adulthood significantly increased from one ACE (aOR, 1.29, 95%CI, 1.22-1.37) to four or more ACEs (1.95, 95%CI, 1.73-2.19).Conclusions: Single and cumulative ACEs are significantly associated with reporting of chronic pain and pain-related disability as an adult.

Previous meta-analyses highlighted the negative impact of adverse childhood experiences on physical, psychological, and behavioural health across the lifespan.We found exposure to any direct adverse childhood experience, i.e. childhood sexual, physical, emotional abuse, or neglect alone or combined, increased the risk of reporting chronic pain and pain-related disability in adulthood.The risk of reporting chronic painful disorders increased with increasing numbers of adverse childhood experiences.

Sex Differences in the Serum Proteomic Profile During Acute Low Back Pain-A Preliminary Study of the Relationship to Future Low Back Pain.

The molecular processes driving the transition from acute to chronic low back pain (LBP) remain poorly understood and are likely to be sexually dimorphic. This study aimed to explore sex differences in the serum proteomic profile of people experiencing an acute LBP episode and determine if serum protein concentrations were associated with three-month outcome. Serum samples were collected through venepuncture from 30 female and 29 male participants experiencing an acute LBP episode. Serum samples underwent trypsin digestion and fractionation using hydrophobic interaction chromatography and were then analysed using mass-spectrometry. Mass-spectrometry spectra were searched in the Swissprot database for protein identification. Sex differences in protein abundance changes were evident upon inspection of fold changes. Multivariable data analysis identified 21 serum proteins during the acute episode that correctly classified 93% of males and 23 serum proteins that correctly classified 90% of females with ongoing LBP at 3 months. Pathway analysis suggested the differentially expressed proteins during acute LBP were frequently involved in immune, inflammatory, complement, or coagulation responses. This data provides preliminary evidence that biological processes during an acute LBP episode may contribute to the resolution, or persistence, of LBP symptoms at 3 months, however, these processes differ between males and females. PERSPECTIVE: Differential expression of serum proteins was observed between male and female participants during an acute LBP episode. This preliminary work provides a foundation for future research targeting distinct immune system processes in males and females that may interfere with the transition from acute to chronic LBP.

Surgical Porcine Model of Chronic Myocardial Ischemia Treated by Exosome-laden Collagen Patch and Off-pump Coronary Artery Bypass Graft.

Chronic myocardial ischemia resulting from progressive coronary artery stenosis leads to hibernating myocardium (HIB), defined as myocardium that adapts to reduced oxygen availability by reducing metabolic activity, thereby preventing irreversible cardiomyocyte injury and infarction. This is distinct from myocardial infarction, as HIB has the potential for recovery with revascularization. Patients with significant coronary artery disease (CAD) experience chronic ischemia, which puts them at risk for heart failure and sudden death. The standard surgical intervention for severe CAD is coronary artery bypass graft surgery (CABG), but it has been shown to be an imperfect therapy, yet no adjunctive therapies exist to recover myocytes adapted to chronic ischemia. To address this gap, a surgical model of HIB using porcine that is amenable to CABG and mimics the clinical scenario was used. The model involves two surgeries. The first operation involves implanting a 1.5 mm rigid constrictor on the left anterior descending (LAD) artery. As the animal grows, the constrictor gradually causes significant stenosis resulting in reduced regional systolic function. Once the stenosis reaches 80%, the myocardial flow and function are impaired, creating HIB. An off-pump CABG is then performed with the left internal mammary artery (LIMA) to revascularize the ischemic region. The animal recovers for one month to allow for optimal myocardial improvement prior to sacrifice. This allows for physiologic and tissue studies of different treatment groups. This animal model demonstrates that cardiac function remains impaired despite CABG, suggesting the need for novel adjunctive interventions. In this study, a collagen patch embedded with mesenchymal stem cell (MSC)-derived exosomes was developed, which can be surgically applied to the epicardial surface distal to LIMA anastomosis. The material conforms to the epicardium, is absorbable, and provides the scaffold for the sustained release of signaling factors. This regenerative therapy can stimulate myocardial recovery that does not respond to revascularization alone. This model translates to the clinical arena by providing means of physiological and mechanistic explorations regarding recovery in HIB.

Genome wide association joint analysis reveals 99 risk loci for pain susceptibility and pleiotropic relationships with psychiatric, metabolic, and immunological traits.

Chronic pain is at epidemic proportions in the United States, represents a significant burden on our public health system, and is coincident with a growing opioid crisis. While numerous genome-wide association studies have been reported for specific pain-related traits, many of these studies were underpowered, and the genetic relationship among these traits remains poorly understood. Here, we conducted a joint analysis of genome-wide association study summary statistics from seventeen pain susceptibility traits in the UK Biobank. This analysis revealed 99 genome-wide significant risk loci, 65 of which overlap loci identified in earlier studies. The remaining 34 loci are novel. We applied leave-one-trait-out meta-analyses to evaluate the influence of each trait on the joint analysis, which suggested that loci fall into four categories: loci associated with nearly all pain-related traits; loci primarily associated with a single trait; loci associated with multiple forms of skeletomuscular pain; and loci associated with headache-related pain. Overall, 664 genes were mapped to the 99 loci by genomic proximity, eQTLs, and chromatin interaction and ~15% of these genes showed differential expression in individuals with acute or chronic pain compared to healthy controls. Risk loci were enriched for genes involved in neurological and inflammatory pathways. Genetic correlation and two-sample Mendelian randomization indicated that psychiatric, metabolic, and immunological traits mediate some of these effects.

Stem cell-derived exosome patch with coronary artery bypass graft restores cardiac function in chronically ischemic porcine myocardium.

OBJECTIVE: This study aimed to investigate whether or not the application of a stem cell-derived exosome-laden collagen patch (EXP) during coronary artery bypass grafting (CABG) can recover cardiac function by modulating mitochondrial bioenergetics and myocardial inflammation in hibernating myocardium (HIB), which is defined as myocardium with reduced blood flow and function that retains viability and variable contractile reserve. METHODS: In vitro methods involved exposing H9C2 cardiomyocytes to hypoxia followed by normoxic coculture with porcine mesenchymal stem cells. Mitochondrial respiration was measured using Seahorse assay. GW4869, an exosomal release antagonist, was used to determine the effect of mesenchymal stem cells-derived exosomal signaling on cardiomyocyte recovery. Total exosomal RNA was isolated and differential micro RNA expression determined by sequencing. In vivo studies comprised 48 Yorkshire-Landrace juvenile swine (6 normal controls, 17 HIB, 19 CABG, and 6 CABG + EXP), which were compared for physiologic and metabolic changes. HIB was created by placing a constrictor on the proximal left anterior descending artery, causing significant stenosis but preserved viability by 12 weeks. CABG was performed with or without mesenchymal stem cells-derived EXP application and animals recovered for 4 weeks. Before terminal procedure, cardiac magnetic resonance imaging at rest, and with low-dose dobutamine, assessed diastolic relaxation, systolic function, graft patency, and myocardial viability. Tissue studies of inflammation, fibrosis, and mitochondrial morphology were performed posttermination. RESULTS: In vitro data demonstrated improved cardiomyocyte mitochondrial respiration upon coculture with MSCs that was blunted when adding the exosomal antagonist GW4869. RNA sequencing identified 8 differentially expressed micro RNAs in normoxia vs hypoxia-induced exosomes that may modulate the expression of key mitochondrial (peroxisome proliferator-activator receptor gamma coactivator 1-alpha and adenosine triphosphate synthase) and inflammatory mediators (nuclear factor kappa-light-chain enhancer of activated B cells, interferon gamma, and interleukin 1ß). In vivo animal magnetic resonance imaging studies demonstrated regional systolic function and diastolic relaxation to be improved with CABG + EXP compared with HIB (P = .02 and P = .02, respectively). Histologic analysis showed increased interstitial fibrosis and inflammation in HIB compared with CABG + EXP. Electron microscopy demonstrated increased mitochondrial area, perimeter, and aspect ratio in CABG + EXP compared with HIB or CABG alone (P < .0001). CONCLUSIONS: Exosomes recovered cardiomyocyte mitochondrial respiration and reduced myocardial inflammation through paracrine signaling, resulting in improved cardiac function.

Establishment of Skeletal Myogenic Progenitors from Non-Human Primate Induced Pluripotent Stem Cells.

Pluripotent stem (PS) cells enable the scalable production of tissue-specific derivatives with therapeutic potential for various clinical applications, including muscular dystrophies. Given the similarity to human counterparts, the non-human primate (NHP) is an ideal preclinical model to evaluate several questions, including delivery, biodistribution, and immune response. While the generation of human-induced PS (iPS)-cell-derived myogenic progenitors is well established, there have been no data for NHP counterparts, probably due to the lack of an efficient system to differentiate NHP iPS cells towards the skeletal muscle lineage. Here, we report the generation of three independent Macaca fascicularis iPS cell lines and their myogenic differentiation using PAX7 conditional expression. The whole-transcriptome analysis confirmed the successful sequential induction of mesoderm, paraxial mesoderm, and myogenic lineages. NHP myogenic progenitors efficiently gave rise to myotubes under appropriate in vitro differentiation conditions and engrafted in vivo into the TA muscles of NSG and FKRP-NSG mice. Lastly, we explored the preclinical potential of these NHP myogenic progenitors in a single wild-type NHP recipient, demonstrating engraftment and characterizing the interaction with the host immune response. These studies establish an NHP model system through which iPS-cell-derived myogenic progenitors can be studied.

Stiffness and axial pain are associated with the progression of calcification in a mouse model of diffuse idiopathic skeletal hyperostosis.

BACKGROUND: Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by progressive calcification of spinal tissues; however, the impact of calcification on pain and function is poorly understood. This study examined the association between progressive ectopic spine calcification in mice lacking equilibrative nucleoside transporter 1 (ENT1-/-), a preclinical model of DISH, and behavioral indicators of pain. METHODS: A longitudinal study design was used to assess radiating pain, axial discomfort, and physical function in wild-type and ENT1-/- mice at 2, 4, and 6 months. At endpoint, spinal cords were isolated for immunohistochemical analysis of astrocytes (GFAP), microglia (IBA1), and nociceptive innervation (CGRP). RESULTS: Increased spine calcification in ENT1-/- mice was associated with reductions in flexmaze exploration, vertical activity in an open field, and self-supporting behavior in tail suspension, suggesting flexion-induced discomfort or stiffness. Grip force during the axial stretch was also reduced in ENT1-/- mice at 6 months of age. Increased CGRP immunoreactivity was detected in the spinal cords of female and male ENT1-/- mice compared to wild-type. GFAP- and IBA1-immunoreactivity were increased in female ENT1-/- mice compared to wild-type, suggesting an increase in nociceptive innervation. CONCLUSION: These data suggest that ENT1-/- mice experience axial discomfort and/or stiffness and importantly that these features are detected during the early stages of spine calcification.

An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium.

Diastolic dysfunction persists despite coronary artery bypass graft surgery (CABG) in patients with hibernating myocardium (HIB). We studied whether the adjunctive use of a mesenchymal stem cells (MSCs) patch during CABG improves diastolic function by reducing inflammation and fibrosis. HIB was induced in juvenile swine by placing a constrictor on the left anterior descending (LAD) artery, causing myocardial ischemia without infarction. At 12 weeks, CABG was performed using the left-internal-mammary-artery (LIMA)-to-LAD graft with or without placement of an epicardial vicryl patch embedded with MSCs, followed by four weeks of recovery. The animals underwent cardiac magnetic resonance imaging (MRI) prior to sacrifice, and tissue from septal and LAD regions were collected to assess for fibrosis and analyze mitochondrial and nuclear isolates. During low-dose dobutamine infusion, diastolic function was significantly reduced in HIB compared to the control, with significant improvement after CABG + MSC treatment. In HIB, we observed increased inflammation and fibrosis without transmural scarring, along with decreased peroxisome proliferator-activated receptor-gamma coactivator (PGC1α), which could be a possible mechanism underlying diastolic dysfunction. Improvement in PGC1α and diastolic function was noted with revascularization and MSCs, along with decreased inflammatory signaling and fibrosis. These findings suggest that adjuvant cell-based therapy during CABG may recover diastolic function by reducing oxidant stress-inflammatory signaling and myofibroblast presence in the myocardial tissue.

Seven-year distress trajectories in uveal melanoma survivors.

OBJECTIVE: Severe or persistent distress is associated with poorer quality of life in cancer survivors. Distress follows distinct trajectories within different population subgroups. Identifying characteristics and causes of trajectories can assist intervention development and targeting. In a 7-year study of uveal melanoma survivors, we aimed to characterize anxiety, depression, and fear of cancer recurrence (FCR) trajectories, and identify whether concerns about symptoms and functional problems over the first 3 years of survivorship predict memberships of high distress trajectories. METHOD: In a closed cohort study, we used growth mixture modeling (GMM) to identify statistically optimal trajectories over 6-, 12-, 24-, 36-, 48-, 60-, 72-, and 84-month time point posttreatment in 475 patients. We then regressed trajectory memberships onto a 3-year series of measures of concerns about symptoms and functional problems, controlling demographic, clinical, and 6-month anxiety, depression, or FCR indicators. RESULTS: Anxiety, depression, and FCR were represented by two-class linear GMMs. The majority scored consistently low, but 17.5% showed consistently elevated anxiety, 10.9% consistently elevated depression, and 19.4% consistently elevated FCR. Higher anxiety trajectory membership was predicted by greater concerns about symptoms at 6 and 24 months, higher depression trajectory membership by symptoms at 24 months, and higher FCR trajectory membership by symptoms at 6 and 24 months and functional problems at 12 months. CONCLUSIONS: Much of the burden of persistent distress in cancer patients falls on a small proportion of survivors. Concerns about symptoms and functional problems are potential risk factors for distress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The Canadian version of the National Institutes of Health minimum dataset for chronic low back pain research: reference values from the Quebec Low Back Pain Study.

ABSTRACT: The National Institutes of Health (NIH) minimum dataset for chronic low back pain (CLBP) was developed in response to the challenge of standardizing measurements across studies. Although reference values are critical in research on CLBP to identify individuals and communities at risk of poor outcomes such as disability, no reference values have been published for the Quebec (Canada) context. This study was aimed to (1) provide reference values for the Canadian version of the NIH minimum dataset among individuals with CLBP in Quebec, both overall and stratified by gender, age, and pain impact stratification (PIS) subgroups, and (2) assess the internal consistency of the minimum data set domains (pain interference, physical function, emotional distress or depression, sleep disturbance, and PIS score). We included 2847 individuals living with CLBP who completed the baseline web survey of the Quebec Low Back Pain Study (age: 44.0 ± 11.2 years, 48.1% women) and were recruited through social media and healthcare settings. The mean score was 6.1 ± 1.8 for pain intensity. Pain interference, physical function, emotional distress or depression, sleep disturbance, and PIS scores were 12.9 ± 4.1, 14.4 ± 3.9, 9.8 ± 4.4, 13.0 ± 3.6, and 26.4 ± 6.6, respectively. Emotional distress or depression showed floor effects. Good-to-excellent internal consistency was found overall and by language, gender, and age subgroups for all domains (alpha: 0.81-0.93) and poor-to-excellent internal consistency for PIS subgroups (alpha: 0.59-0.91). This study presents reference values and recommendations for using the Canadian version of the NIH minimum dataset for CLBP that can be useful for researchers and clinicians.

Macrophages and Intervertebral Disc Degeneration.

The intervertebral disc (IVD) aids in motion and acts to absorb energy transmitted to the spine. With little inherent regenerative capacity, degeneration of the intervertebral disc results in intervertebral disc disease, which contributes to low back pain and significant disability in many individuals. Increasing evidence suggests that IVD degeneration is a disease of the whole joint that is associated with significant inflammation. Moreover, studies show elevated macrophage accumulation within the IVD with increasing levels of disease severity; however, we still need to understand the roles, be they causative or consequential, of macrophages during the degenerative process. In this narrative review, we discuss hallmarks of IVD degeneration, showcase evidence of macrophage involvement during disc degeneration, and explore burgeoning research aimed at understanding the molecular pathways regulating macrophage functions during intervertebral disc degeneration.

Fear of cancer recurrence and adverse cancer treatment outcomes: predicting 2- to 5-year fear of recurrence from post-treatment symptoms and functional problems in uveal melanoma survivors.

OBJECTIVE: The fear of cancer recurrence (FCR) in later survivorship can lead to poorer mental health, quality of life and physical and functional recovery. Later-occurring FCR may be a consequence of late-emerging physical symptoms and functional problems from cancer or its treatment. Based on the self-regulation model, we predicted that persistent or escalating symptoms and functional problems would prospectively predict FCR observed 2-5 years after diagnosis and treatment. METHODS: This is a five-year study of 708 uveal melanoma (UM) patients, measuring self-reported visual and ocular symptoms, functional problems and FCR at 6, 12, 24, 36, 48 and 60 months post-diagnosis. A mixed measures design over four levels with observations staggered to represent prospective prediction. Criterion variables were FCR at 24, 36, 48 and 60 months. Predictors were symptom and function scores measured at the previous two observations to FCR. Controls were FCR measured at the previous observation to the criterion FCR measure and demographic, clinical and treatment variables. RESULTS: Linear mixed modelling showed that FCR was uniquely predicted by enduring symptoms, those that emerged two observations previously, but not symptoms arising at the previous observation. FCR was predicted by functional problems, which emerged in the observation prior to FCR, but not the observation previous to that. CONCLUSIONS: Persistent or emerging post-treatment symptoms and functional limitations are probable risk factors for late-occurring FCR in UM survivors. IMPLICATIONS FOR CANCER SURVIVORS: Monitoring symptoms and functional limitations assists in identifying at-risk survivors and targeting preventive interventions. Self-regulation theory suggests that helping survivors to more realistically appraise symptoms and functional problems may prevent FCR.

Persistent diastolic dysfunction in chronically ischemic hearts following coronary artery bypass graft.

OBJECTIVE: A porcine model was used to study diastolic dysfunction in hibernating myocardium (HM) and recovery with coronary artery bypass surgery (CABG). METHODS: HM was induced in Yorkshire-Landrace juvenile swine (n = 30) by placing a c-constrictor on left anterior descending artery causing chronic myocardial ischemia without infarction. At 12 weeks, animals developed the HM phenotype and were either killed humanely (HIB group; n = 11) or revascularized with CABG and allowed 4 weeks of recovery (HIB+CABG group; n = 19). Control pigs were matched for weight, age, and sex to the HIB group. Before the animals were killed humanely, cardiac magnetic resonance imaging (MRI) was done at rest and during a low-dose dobutamine infusion. Tissue was obtained for histologic and proinflammatory biomarker analyses. RESULTS: Diastolic peak filling rate was lower in HIB compared with control (5.4 ± 0.7 vs 6.7 ± 1.4 respectively, P = .002), with near recovery with CABG (6.3 ± 0.8, P = .06). Cardiac MRI confirmed preserved global systolic function in all groups. Histology confirmed there was no transmural infarction but showed interstitial fibrosis in the endomysium in both the HIB and HIB+CABG groups compared with normal myocardium. Alpha-smooth muscle actin stain identified increased myofibroblasts in HM that were less apparent post-CABG. Cytokine and proteomic studies in HM showed decreased peroxisome proliferator-activator receptor gamma coactivator 1-alpha (PGC1-α) expression but increased expression of granulocyte-macrophage colony-stimulating factor and nuclear factor kappa-light-chain enhancer of activated B cells (NFκB). Following CABG, PGC1-α and NFκB expression returned to control whereas granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, and interferon gamma remained increased. CONCLUSIONS: In porcine model of HM, increased NFκB expression, enhanced myofibroblasts, and collagen deposition along with decreased PGC1-α expression were observed, all of which tended toward normal with CABG. Estimates of impaired relaxation with MRI within HM during increased workload persisted despite CABG, suggesting a need for adjuvant therapies during revascularization.

Predictors of emotional distress in uveal melanoma survivors: a systematic review.

Uveal melanoma (UM) survivors can experience significant emotional distress, although the factors underpinning this are poorly understood. Systematic reviews of distress in UM only include cross-sectional studies, thereby limiting our understanding of causal factors. This review identified prospective clinical, demographic, social and psychological predictors of distress in UM survivors. A systematic search of the literature for English language prospective studies was conducted. Thirteen papers, reporting data from seven unique datasets were included in a narrative synthesis of the results. Younger age (3 studies from 3 datasets), physical health (including visual impairment, ocular symptoms, and other UM-related factors; 3 studies from 3 datasets), and psychological factors (mainly baseline distress; 3 studies from 3 datasets and worry about recurrence; 2 studies from 2 datasets), significantly predicted distress. There was no consistent evidence for other demographic, clinical or social variables (significant in <50% of datasets). Generally, the quality of the papers was adequate. However, attrition rates were high or not reported in over half of the included studies. The findings of this review emphasise the importance of attempts to prevent and recognise distress immediately post-diagnosis of UM. Particular focus should be given to younger patients, those with physical and psychological health difficulties at the time of diagnosis, and those who develop adverse treatment symptoms during survivorship. More research into potential social and psychological variables and their role in predicting distress in survivors is recommended.