Energy Expenditure as a Function of Activity Level After Spinal Cord Injury: The Need for Tetraplegia-Specific Energy Balance Guidelines

The World Health Organization recognizes obesity as a global and increasing problem for the general population. Because of their reduced physical functioning, people with spinal cord injury (SCI) face additional challenges for maintaining an appropriate whole body energy balance, and the majority with SCI are overweight or obese. SCI also reduces exercise capacity, particularly in those with higher-level injury (tetraplegia). Tetraplegia-specific caloric energy expenditure (EE) data is scarce. Therefore, we measured resting and exercise-based energy expenditure in participants with tetraplegia and explored the accuracy of general population-based energy use predictors. Body composition and resting energy expenditure (REE) were measured in 25 adults with tetraplegia (C4/5 to C8) and in a sex-age-height matched group. Oxygen uptake, carbon dioxide production, heart rate, perceived exertion, and exercise intensity were also measured in 125 steady state exercise trials. Those with motor-complete tetraplegia, but not controls, had measured REE lower than predicted (mean = 22% less, p < 0.0001). REE was also lower than controls when expressed per kilogram of lean mass. Nine had REE below 1200 kcal/day. We developed a graphic compendium of steady state EE during arm ergometry, wheeling, and hand-cycling. This compendium is in a format that can be used by persons with tetraplegia for exercise prescription (calories, at known absolute intensities). EE was low (55–450 kcal/h) at the intensities participants with tetraplegia were capable of maintaining. If people with tetraplegia followed SCI-specific activity guidelines (220 min/week) at the median intensities we measured, they would expend 563–1031 kcal/week. Participants with tetraplegia would therefore require significant time (4 to over 20 h) to meet a weekly 2000 kcal exercise target. We estimated total daily EE for a range of activity levels in tetraplegia and compared them to predicted values for the general population. Our analysis indicated that the EE values for sedentary through moderate levels of activity in tetraplegia fall well below predicted sedentary levels of activity for the general population. These findings help explain sub-optimal responses to exercise interventions after tetraplegia, and support the need to develop tetraplegia-specific energy-balance guidelines that reflects their unique EE situation

Mesenchymal stem cell therapy in hypertrophic and keloid scars.

Funder: University of CambridgeScars are the normal outcome of wound repair and involve a co-ordinated inflammatory and fibrotic process. When a scar does not resolve, uncontrolled chronic inflammation can persist and elicits excessive scarring that leads to a range of abnormal phenotypes such as hypertrophic and keloid scars. These pathologies result in significant impairment of quality of life over a long period of time. Existing treatment options are generally unsatisfactory, and there is mounting interest in innovative cell-based therapies. Despite the interest in mesenchymal stem cells (MSCs), there is yet to be a human clinical trial that investigates the potential of MSCs in treating abnormal scarring. A synthesis of existing evidence of animal studies may therefore provide insight into the barriers to human application. The aim of this PRISMA systematic review was to evaluate the effectiveness of MSC transplantation in the treatment of hypertrophic and keloid scars in in vivo models. A total of 11 case-control studies were identified that treated a total of 156 subjects with MSCs or MSC-conditioned media. Ten studies assessed hypertrophic scars, and one looked at keloid scars. All studies evaluated scars in terms of macroscopic and histological appearances and most incorporated immunohistochemistry. The included studies all found improvements in the above outcomes with MSC or MSC-conditioned media without complications. The studies reviewed support a role for MSC therapy in treating scars that needs further exploration. The transferability of these findings to humans is limited by factors such as the reliability and validity of the disease model, the need to identify the optimal MSC cell source, and the outcome measures employed

Reporting of health equity considerations in cluster and individually randomized trials

CITATION: Petkovic, J., et al. 2020. Reporting of health equity considerations in cluster and individually randomized trials. Trials, 21:308, doi:10.1186/s13063-020-4223-5.The original publication is available at https://trialsjournal.biomedcentral.comBackground: The randomized controlled trial (RCT) is considered the gold standard study design to inform decisions about the effectiveness of interventions. However, a common limitation is inadequate reporting of the applicability of the intervention and trial results for people who are “socially disadvantaged” and this can affect policy-makers’ decisions. We previously developed a framework for identifying health-equity-relevant trials, along with a reporting guideline for transparent reporting. In this study, we provide a descriptive assessment of healthequity considerations in 200 randomly sampled equity-relevant trials. Methods: We developed a search strategy to identify health-equity-relevant trials published between 2013 and 2015. We randomly sorted the 4316 records identified by the search and screened studies until 100 individually randomized (RCTs) and 100 cluster randomized controlled trials (CRTs) were identified. We developed and pilottested a data extraction form based on our initial work, to inform the development of our reporting guideline for equity-relevant randomized trials. Results: In total, 39 trials (20%) were conducted in a low- and middle-income country and 157 trials (79%) in a high-income country focused on socially disadvantaged populations (78% CRTs, 79% RCTs). Seventy-four trials (37%) reported a subgroup analysis across a population characteristic associated with disadvantage (25% CRT, 49% RCTs), with 19% of included studies reporting subgroup analyses across sex, 9% across race/ethnicity/culture, and 4% across socioeconomic status. No subgroup analyses were reported for place of residence, occupation, religion, education, or social capital. One hundred and forty-one trials (71%) discussed the applicability of their results to one or more socially disadvantaged populations (68% of CRT, 73% of RCT). Discussion: In this set of trials, selected for their relevance to health equity, data that were disaggregated for socially disadvantaged populations were rarely reported. We found that even when the data are available, opportunities to analyze health-equity considerations are frequently missed. The recently published equity extension of the Consolidated Reporting Standards for Randomized Trials (CONSORT-Equity) may help improve delineation of hypotheses related to socially disadvantaged populations, and transparency and completeness of reporting of health-equity considerations in RCTs. This study can serve as a baseline assessment of the reporting of equity considerations.https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-4223-5Publisher's versio

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Mesenchymal stem cell therapy in hypertrophic and keloid scars.

Funder: University of CambridgeScars are the normal outcome of wound repair and involve a co-ordinated inflammatory and fibrotic process. When a scar does not resolve, uncontrolled chronic inflammation can persist and elicits excessive scarring that leads to a range of abnormal phenotypes such as hypertrophic and keloid scars. These pathologies result in significant impairment of quality of life over a long period of time. Existing treatment options are generally unsatisfactory, and there is mounting interest in innovative cell-based therapies. Despite the interest in mesenchymal stem cells (MSCs), there is yet to be a human clinical trial that investigates the potential of MSCs in treating abnormal scarring. A synthesis of existing evidence of animal studies may therefore provide insight into the barriers to human application. The aim of this PRISMA systematic review was to evaluate the effectiveness of MSC transplantation in the treatment of hypertrophic and keloid scars in in vivo models. A total of 11 case-control studies were identified that treated a total of 156 subjects with MSCs or MSC-conditioned media. Ten studies assessed hypertrophic scars, and one looked at keloid scars. All studies evaluated scars in terms of macroscopic and histological appearances and most incorporated immunohistochemistry. The included studies all found improvements in the above outcomes with MSC or MSC-conditioned media without complications. The studies reviewed support a role for MSC therapy in treating scars that needs further exploration. The transferability of these findings to humans is limited by factors such as the reliability and validity of the disease model, the need to identify the optimal MSC cell source, and the outcome measures employed

Chondroitinase gene therapy improves upper limb function following cervical contusion injury

Chondroitin sulphate proteoglycans (CSPGs) are known to be important contributors to the intensely inhibitory environment that prevents tissue repair and regeneration following spinal cord injury. The bacterial enzyme chondroitinase ABC (ChABC) degrades these inhibitory molecules and has repeatedly been shown to promote functional recovery in a number of spinal cord injury models. However, when used to treat more traumatic and clinically relevant spinal contusion injuries, findings with the ChABC enzyme have been inconsistent. We recently demonstrated that delivery of mammalian-compatible ChABC via gene therapy led to sustained and widespread digestion of CSPGs, resulting in significant functional repair of a moderate thoracic contusion injury in adult rats. Here we demonstrate that chondroitinase gene therapy significantly enhances upper limb function following cervical contusion injury, with improved forelimb ladder performance and grip strength as well as increased spinal conduction through the injury site and reduced lesion pathology. This is an important addition to our previous findings as improving upper limb function is a top priority for spinal injured patients. Additionally great importance is placed on replication in the spinal cord injury field. That chondroitinase gene therapy has now been shown to be efficacious in contusion models at either thoracic or cervical level is an important step in the further development of this promising therapeutic strategy towards the clinic. (C) 2015 The Authors. Published by Elsevier Inc

Patient-reported pain is central to OMERACT rheumatology core measurement sets

This article provides evidence from the OMERACT (Outcome Measures in RheumAtology Clinical Trials) consensus conferences on patient-reported pain as a key outcome measure for most rheumatologic diseases, including rheumatoid arthritis, osteoarthritis, osteoporosis, back disorders, ankylosing spondylitis, and lupus. These core sets have been endorsed internationally by the World Health Organization, the International League Against Rheumatism, the US National Osteoporosis Foundation, and the OsteoArthritis Research Society International (OARSI). Future research will assess methods for improving interpretability of pain outcomes for patients and clinicians. These methods include determining minimal clinically important differences and number needed to treat (NNT) for continuous outcomes such as pain. Copyrigh

A Quality Improvement Project to Improve Family Recognition of Medical Team Member Roles

OBJECTIVE: Previous studies have shown that inpatients and families in academic settings have a limited ability to recall either their medical team members or the roles of those members. This is an important issue for patient and family satisfaction as well as patient safety. The objective of this study was to increase families’ recognition of medical team members’ roles. METHODS: We established a multidisciplinary quality improvement leadership team, measured family recognition of medical team members and their roles, and conducted 2 PDSA (Plan-Do-Study-Act) cycles. The first intervention was standardization of the content and delivery of our verbal team introductions to ensure inclusion of essential elements and family engagement. The second intervention was addition of an informational white board in each patient room. The prospective study included 105 families in the preintervention phase, 103 post-PDSA cycle 1, and 92 post-PDSA cycle 2. RESULTS: After conduction of 2 PDSA cycles, the recognition of the attending role increased from 49% to 87% (P = .000), the resident role from 39% to 73% (P = .000), and the medical student from 75% to 89% (P = .038). CONCLUSIONS: The multidisciplinary quality improvement model was effective in improving family recognition of the roles of attending physicians, resident physicians, and medical students. Consistent attention to engaging the families and explaining our roles as well as providing informational white boards are effective interventions to facilitate this process

Evaluating the potential of gold, silver, and silica nanoparticles to saturate mononuclear phagocytic system tissues under repeat dosing conditions

Abstract Background As nanoparticles (NPs) become more prevalent in the pharmaceutical industry, questions have arisen from both industry and regulatory stakeholders about the long term effects of these materials. This study was designed to evaluate whether gold (10 nm), silver (50 nm), or silica (10 nm) nanoparticles administered intravenously to mice for up to 8 weeks at doses known to be sub-toxic (non-toxic at single acute or repeat dosing levels) and clinically relevant could produce significant bioaccumulation in liver and spleen macrophages. Results Repeated dosing with gold, silver, and silica nanoparticles did not saturate bioaccumulation in liver or spleen macrophages. While no toxicity was observed with gold and silver nanoparticles throughout the 8 week experiment, some effects including histopathological and serum chemistry changes were observed with silica nanoparticles starting at week 3. No major changes in the splenocyte population were observed during the study for any of the nanoparticles tested. Conclusions The clinical impact of these changes is unclear but suggests that the mononuclear phagocytic system is able to handle repeated doses of nanoparticles