Age, Race, Ethnicity, and Sex of Participants in Clinical Trials Focused on Chronic Pain.

There is limited data on equitable inclusion in chronic pain trials. We aimed to 1) identify the frequency of reporting age, race, ethnicity, and sex in clinical trials targeting chronic pain, and 2) compare sociodemographic representation to the United States (US) population. We examined US-based intervention trials for chronic pain initiated between 2007 and 2021 and registered on ClinicalTrials.gov. We 1) assessed the frequency of reporting each demographic variable, 2) compared representation with US population estimates, and 3) explored change in reporting over time. Of 501 clinical trials, the frequency of reporting was as follows: 36.9% reported older adults, 54.3% reported race, 37.4% reported ethnicity, and 100% reported sex. Rates of race and ethnicity reporting increased, but older adult age reporting decreased over time (ps < .00001). Compared to 2020 US population estimates, there was an equitable representation of older adults, under-representation of individuals identifying as American Indian or Alaska Native (.8% vs .6%), Asian (5.6% vs 2.9%), Black or African American (12.6% vs 12.2%), with more than one race (2.9% vs 1.2%), and Hispanic/Latino (16.9% vs 14.1%). There was an over-representation of individuals identifying as Native Hawaiian or Pacific Islander (.2% vs .5%) or White (70.4% vs 72.9%), and of females (50.8% vs 68.4%). Some representation rates varied by chronic pain condition. Reporting of older adult age, race, and ethnicity was low in chronic pain trials in ClinicalTrials.gov, reinforcing the need for adhering to reporting guidelines. Representation varied across trials compared with US population data, particularly among those identifying as Hispanic/Latino and certain minority racial groups. PERSPECTIVE: Despite initiatives to increase the reporting of demographic information, doing so in clinical pain trials is far from ubiquitous. Moreover, efforts to improve diversity in these trials continue to be insufficient. Indeed, Black, Indigenous, and People of Color (BIPOC) remain under-represented in clinical pain trials.

Characterization of adult human skeletal cells in different tissues reveals a CD90+CD34+ periosteal stem/progenitor population.

The periosteum plays a crucial role in bone healing and is an important source of skeletal stem and progenitor cells. Recent studies in mice indicate that diverse populations of skeletal progenitors contribute to growth, homeostasis and healing. Information about the in vivo identity and diversity of skeletal stem and progenitor cells in different compartments of the adult human skeleton is limited. In this study, we compared non-hematopoietic populations in matched tissues from the femoral head and neck of 21 human participants using spectral flow cytometry of freshly isolated cells. High-dimensional clustering analysis indicated significant differences in marker distribution between periosteum, articular cartilage, endosteum and bone marrow populations, and identified populations that were highly enriched or unique to specific tissues. Periosteum-enriched markers included CD90 and CD34. Articular cartilage, which has very poor regenerative potential, showed enrichment of multiple markers, including the PDPN+CD73+CD164+CD146- population previously reported to represent human skeletal stem cells. We further characterized periosteal populations by combining CD90 with other strongly expressed markers. CD90+CD34+ cells sorted directly from periosteum showed significant colony-forming unit fibroblasts (CFU-F) enrichment, rapid expansion, and consistent multi-lineage differentiation of clonal populations in vitro. In situ, CD90+CD34+ cells include a perivascular population in the outer layer of the periosteum and non-perivascular cells closer to the bone surface. CD90+ cells are also highly enriched for CFU-F in bone marrow and endosteum, but not articular cartilage. In conclusion, our study indicates considerable diversity in the non-hematopoietic cell populations in different tissue compartments within the adult human skeleton, and suggests that periosteal progenitor cells reside within the CD90+CD34+ population.

Evaluation of the MOVE online exercise programme for young people aged 13-30.

PURPOSE: To evaluate the MOVE exercise programme in supporting the recovery of young people affected by cancer. METHODS: Participants in an 8-week exercise rehabilitation programme delivered online by cancer rehabilitation specialists completed self-reported questionnaires at baseline and after programme completion. Assessments included cancer-related fatigue (FACIT fatigue scale) and health-related quality of life (EORTC-QLC-30). Qualitative data were provided through written accounts of participant experiences and underwent content analysis. RESULTS: Seventy-one participants commenced the exercise rehabilitation programme and 57 completed the programme and provided data for analysis (63% female; median age 22 years). Statistically significant improvements were observed in post-programme scores for all measured outcomes (cancer-related fatigue, quality of life, physical functioning, role functioning, emotional functioning). Content analysis of written experiences generated ten unique codes. The highest frequency codes were enjoyment (n = 34), motivation (n = 14) and fitness (n = 13). CONCLUSIONS: These findings indicate feasibility of delivery, acceptability to patients and physical and psychological benefits of a personalised online exercise rehabilitation programme for young people living with and beyond cancer. Further research involving a control arm and long-term follow-up would be beneficial. IMPLICATIONS FOR CANCER SURVIVORS: These results support the inclusion of a personalised exercise programme as part of cancer rehabilitation for young people living with and beyond cancer.

PSA-NCAM Regulatory Gene Expression Changes in the Alzheimer's Disease Entorhinal Cortex Revealed with Multiplexed in situ Hybridization.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia and is characterized by a substantial reduction of neuroplasticity. Our previous work demonstrated that neurons involved in memory function may lose plasticity because of decreased protein levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in the entorhinal cortex (EC) of the human AD brain, but the cause of this decrease is unclear. OBJECTIVE: To investigate genes involved in PSA-NCAM regulation which may underlie its decrease in the AD EC. METHODS: We subjected neurologically normal and AD human EC sections to multiplexed fluorescent in situ hybridization and immunohistochemistry to investigate genes involved in PSA-NCAM regulation. Gene expression changes were sought to be validated in both human tissue and a mouse model of AD. RESULTS: In the AD EC, a cell population expressing a high level of CALB2 mRNA and a cell population expressing a high level of PST mRNA were both decreased. CALB2 mRNA and protein were not decreased globally, indicating that the decrease in CALB2 was specific to a sub-population of cells. A significant decrease in PST mRNA expression was observed with single-plex in situ hybridization in middle temporal gyrus tissue microarray cores from AD patients, which negatively correlated with tau pathology, hinting at global loss in PST expression across the AD brain. No significant differences in PSA-NCAM or PST protein expression were observed in the MAPT P301S mouse brain at 9 months of age. CONCLUSION: We conclude that PSA-NCAM dysregulation may cause subsequent loss of structural plasticity in AD, and this may result from a loss of PST mRNA expression. Due PSTs involvement in structural plasticity, intervention for AD may be possible by targeting this disrupted plasticity pathway.

Elective hip arthroplasty rates and related complications in people with diabetes mellitus.

BACKGROUND AND AIMS: Diabetes mellitus (DM), poor glycaemic control and raised body mass index (BMI) have been associated with postoperative complications in arthroplasty, although the relative importance of these factors is unclear. We describe the prevalence of DM in elective hip arthroplasty in a UK centre, and evaluate the impact of these factors. METHODS: We analysed retrospective data for DM patients undergoing arthroplasty over a 6-year period and compared with non-diabetic matched controls (1 DM patient: 5 controls). DM was present in 5.7% of hip arthroplasty patients (82/1443). RESULTS: Postoperative complications occurred in 12.2% of DM patients versus 12.9% of controls (p = 1.000); surgical complications were present in 6.1% of those with DM and 2.4% of controls (p = 0.087), while medical complications occurred in 8.5% of DM patients versus 10.7% of controls (p = 0.692). Complications developed in 23.1% of DM patients with poor glycaemic control (HbA1c > 53 mmol/mol) versus 9.8% with good control (p = 0.169). In DM patients and controls combined, complications occurred in 16.3% of obese patients versus 10.0% of non-obese patients (p = 0.043). In the DM cohort, 13.7% of overweight patients had complications versus 0% with a normal or low BMI (p = 0.587). CONCLUSIONS: DM rates were lower than expected, and glycaemic control was good. Overall complication rates were unrelated to the presence of DM or to glycaemic control, although surgical complications were observed more frequently in those with DM and poor glycaemic control was uncommon within our cohort. Complications were more frequent in those with a higher BMI. Whether some patients with DM but without an increased risk of complications are currently being excluded from surgery requires exploration.

Writing's on the wall: improving the WHO Surgical Safety Checklist.

BACKGROUND AND PROBLEM: The WHO Surgical Safety Checklist has been shown to improve patient safety as well as improving teamwork and communication in theatres. In 2009, it was made a mandatory requirement for all NHS hospitals in England and Wales. The WHO checklist is intended to be adapted to suit local settings and was modified for use in Gloucestershire Hospitals NHS Foundation Trust. In 2018, it was decided to review the use of the adapted WHO checklist and determine whether improvements in compliance and engagement could be achieved. AIM: The aim was to achieve 90% compliance and engagement with the WHO Surgical Safety Checklist by April 2019. METHODS: In April 2018, a prospective observational audit and online survey took place. The results showed compliance for the 'Sign In' section of the checklist was 55% and for the 'Time Out' section was 91%. Engagement by the entire theatre team was measured at 58%. It was proposed to move from a paper checklist to a wall-mounted checklist, to review and refine the items in the checklist and to change the timing of 'Time Out' to ensure it was done immediately prior to knife-to-skin. RESULTS: Following its introduction in September 2018, the new wall-mounted checklist was reaudited. Compliance improved to 91% for 'Sign In' and to 94% for 'Time Out'. Engagement by the entire theatre team was achieved 100% of the time. Feedback was collected, adjustments made and the new checklist was rolled out in stages across all theatres. A reaudit in December 2018 showed compliance improved further, to 99% with 'Sign In' and to 100% with 'Time Out'. Engagement was maintained at 100%. CONCLUSIONS: The aim of the project was met and exceeded. Since April 2019, the new checklist is being used across all theatres in the Trust.

Quantitative immunohistochemical analysis of myeloid cell marker expression in human cortex captures microglia heterogeneity with anatomical context.

Current immunohistochemical methods of studying microglia in the post-mortem human brain do not capture the heterogeneity of microglial function in response to damage and disease. We therefore investigated the expression of eight myeloid cell proteins associated with changes in function alongside Iba1. To study the myeloid cells we used immunohistochemistry on post-mortem human middle temporal gyrus sections from neurologically normal individuals. First we investigated co-labelling between the classical 'activation' marker, HLA-DR and each of the other markers of interest. Significant co-labelling between HLA-DR with CD206, CD32, CD163, or L-Ferritin was observed, although complete overlap of expression of HLA-DR with aforementioned markers was not observed. A qualitative assessment also demonstrated that perivascular macrophages expressed higher levels of the markers of interest we investigated than microglia, suggesting perivascular macrophages show a more phagocytic and antigen presentation state in the human brain. To determine whether the markers of interest were expressed in different functional states, the immunoreactivity for each marker was qualitatively assessed on microglial morphologies. Degenerating marker, L-Ferritin, was specific for dystrophic microglia. We demonstrate that microglial heterogeneity can be investigated in immunohistochemically stain post-mortem human tissue by integrating the single-cell abundance of proteins and cell morphology to infer function.

Patient Perceptions of the Impact of Treatment (Surgery and Radiotherapy) for Soft Tissue Sarcoma.

BACKGROUND AND OBJECTIVES: Treatment for soft tissue sarcoma (STS) is challenging for patients. This study aimed to gain an in-depth understanding of patients' experiences of STS treatment, including whether the sequence of treatment (preoperative or postoperative radiotherapy) influences patient perceptions. METHODS: Face-to-face semi-structured interviews were conducted with nineteen patients who had been treated for STS with surgery and radiotherapy between 2011 and 2016. Topics discussed included perceptions of treatment, social support, and coping mechanisms. Qualitative, inductive, thematic analysis was conducted and structured using the Framework approach. RESULTS: Treatment sequence itself did not appear to cause concern, but uncertainty regarding treatment and side effects could negatively impact participants. Social relationships and individual coping strategies influenced participants' experiences of treatment. CONCLUSIONS: Participants' perceptions of the treatment process varied; the experience was highly individual. It is important to ensure individual psychosocial and information needs are met. In particular, the removal of uncertainty regarding treatment is important in supporting patients undergoing treatment for soft tissue sarcoma.

Neurochemical Characterization of PSA-NCAM+ Cells in the Human Brain and Phenotypic Quantification in Alzheimer's Disease Entorhinal Cortex.

Polysialylated neural cell adhesion molecule (PSA-NCAM) is widely expressed in the adult human brain and facilitates structural remodeling of cells through steric inhibition of intercellular NCAM adhesion. We previously showed that PSA-NCAM immunoreactivity is decreased in the entorhinal cortex in Alzheimer's disease (AD). Based on available evidence, we hypothesized that a loss of PSA-NCAM+ interneurons may underlie this reduction. PSA-NCAM expression by interneurons has previously been described in the human medial prefrontal cortex. Here we used postmortem human brain tissue to provide further evidence of PSA-NCAM+ interneurons throughout the human hippocampal formation and additional cortical regions. Furthermore, PSA-NCAM+ cell populations were assessed in the entorhinal cortex of normal and AD cases using fluorescent double labeling and manual cell counting. We found a significant decrease in the number of PSA-NCAM+ cells per mm2 in layer II and V of the entorhinal cortex, supporting our previous description of reduced PSA-NCAM immunoreactivity. Additionally, we found a significant decrease in the proportion of PSA-NCAM+ cells that co-labeled with NeuN and parvalbumin, but no change in the proportion that co-labeled with calbindin or calretinin. These results demonstrate that PSA-NCAM is expressed by a variety of interneuron populations throughout the brain. Furthermore, that loss of PSA-NCAM expression by NeuN+ cells predominantly contributes to the reduced PSA-NCAM immunoreactivity in the AD entorhinal cortex.

Investigation of Taper Failure in a Contemporary Metal-on-Metal Hip Arthroplasty System Through Examination of Unused and Explanted Prostheses.

BACKGROUND: Large-diameter (≥36-mm) metal-on-metal (MoM) total hip replacements have been shown to fail at an unacceptably high rate. Globally, the DePuy Pinnacle prosthesis was the most widely used device of this type. There is evidence to suggest that one of the main reasons for the poor clinical performance of large-diameter MoM prostheses is the metal debris released from the head-stem taper junction-i.e., taper junction failure. The aim of this study was to investigate variation in the as-manufactured finish of the female taper surface and to determine its influence on material loss. We hypothesized that rougher surfaces with higher relative material peaks would be significantly associated with greater taper wear rates. METHODS: We analyzed 93 Articul/eze femoral head tapers with a 36-mm bearing diameter that had been used in combination with a Corail titanium uncemented stem. The influence of the surface topography of the as-manufactured female taper surface on taper wear was examined by means of a multiple regression model, taking into account other known variables. RESULTS: We identified great variation in the as-manufactured surface finish of the female taper surface, with a range of measured Ra values from 0.14 to 4.20 µm. The roughness of the female taper surface appeared to be the most important variable associated with taper wear (p < 0.001). The best-fitting regression model, including duration in vivo, head offset, reduced peak height (Rpk) value, stem shaft angle, and bearing surface wear rate, explained approximately 44% of the variation in taper wear rates. CONCLUSIONS: We concluded that the roughness of the female taper surface appears to be a significant factor in metal debris release from head-stem taper junctions. CLINICAL RELEVANCE: This study shows evidence that previously unappreciated variations in manufacturing processes may have a major impact on the clinical outcomes of patients.

Distribution of PSA-NCAM in normal, Alzheimer's and Parkinson's disease human brain.

Polysialated neural cell adhesion molecule (PSA-NCAM) is a membrane bound glycoprotein widely expressed during nervous system development. While commonly described in the neurogenic niches of the adult human brain, there is limited evidence of its distribution in other brain regions. PSA-NCAM is an important regulator of cell-cell interactions and facilitates cell migration and plasticity. Recent evidence suggests these functions may be altered in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). This study provides a detailed description of the PSA-NCAM distribution throughout the human brain and quantitatively compares the staining load in cortical regions and sub-cortical structures between the control, AD and PD brain. Our results provide evidence of widespread, yet specific, PSA-NCAM expression throughout the human brain including regions devoid of PSA-NCAM in the rodent brain such as the caudate nucleus (CN) and cerebellum (CB). We also detected a significant reduction in PSA-NCAM load in the entorhinal cortex (EC) of cases that was inversely correlated with hyperphosphorylated tau load. These results demonstrate that PSA-NCAM-mediated structural plasticity may not be limited to neurogenic niches and is conserved in the aged brain. We also provide evidence that PSA-NCAM is reduced in the EC, a region severely affected by AD pathology.

Reprogramming pig fetal fibroblasts reveals a functional LIF signaling pathway.

Distinct signaling pathways are reported to maintain pluripotency in embryo-derived stem cells. Mouse embryonic stem cells (ESCs) respond to leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP)-mediated activity, whereas human ESCs depend upon Fibroblast growth factor (FGF) and activin signaling. In the majority of mammals investigated, however, the signals that support stem cell pluripotency are not well defined, as is evident by the persistent difficulties in maintaining authentic stable ESC lines. Induction of pluripotency by transcription factor-mediated reprogramming could provide an alternative way to produce ESC-like cells from nonpermissive species, and facilitate identification of core ESC signaling requirements. To evaluate the effectiveness of this approach in pigs, we transduced porcine foetal fibroblasts with retroviruses expressing Oct4, Sox2, Klf4, and c-Myc, and maintained the resulting cultures in medium containing either LIF or FGF2. Alkaline phosphatase positive colonies with compact, mouse ESC-like morphology were preferentially recovered using serum-free medium supplemented with LIF. These cell lines expressed the endogenous stem cell transcription factors, OCT4, NANOG, and SOX2, and the cell surface marker SSEA-4, consistent with acquisition of an undifferentiated state. However, restricted differentiation potential, and persistent expression of retroviral transgenes indicated that reprogramming was incomplete. Interestingly, LIF activated both the transcription factor STAT3 and its target gene SOCS3, and stimulated cell growth, indicating functional coupling of the signaling pathway in these cells. This demonstration of LIF-dependence in reprogrammed pig cells supports the notion that the connection between LIF/STAT3 signaling and the core regulatory network of pluripotent stem cells is a conserved pathway in mammals.

Distinct roles for tetraspanins CD9, CD63 and CD81 in the formation of multinucleated giant cells.

Members of the tetraspanin superfamily of proteins are implicated in a variety of complex cell processes including cell fusion. However, the contribution of individual tetraspanins to these processes has proved difficult to define. Here we report the use of recombinant extracellular regions of tetraspanins to investigate the role of specific members of this family in the fusion of monocytes to form multinucleated giant cells (MGC). In contrast to their positive requirement in sperm-egg fusion, previous studies using antibodies and knockout mice have indicated a negative regulatory role for tetraspanins CD9 and CD81 in this process. In an in vitro model of fusion using human monocytes, we have confirmed observations that antibodies to CD9 and CD81 enhance MGC formation; however, in contrast to previous investigations, we found that all members of a panel of antibodies to CD63 inhibited fusion. Moreover, recombinant proteins corresponding to the large extracellular domains (EC2s) of CD63 and CD9 inhibited MGC formation, whereas the EC2s of CD81 and CD151 had no effect. The potent inhibition of fusion and binding of labelled CD63 EC2 to monocytes under fusogenic conditions suggest a direct interaction with a membrane component required for fusion. Our findings indicate that the tetraspanins CD9, CD63 and CD81 are all involved in MGC formation, but play distinct roles.