Background:
Bone marrow aspirate concentrate (BMAC) is increasingly used as a regenerative therapy for musculoskeletal pathological conditions despite limited evidence-based support.
Hypothesis:
BMAC ...will prove feasible, safe, and efficacious for the treatment of pain due to mild to moderate degenerative joint disease of the knee.
Study Design:
Randomized controlled trial; Level of evidence, 2.
Methods:
In this prospective, single-blind, placebo-controlled trial, 25 patients with bilateral knee pain from bilateral osteoarthritis were randomized to receive BMAC into one knee and saline placebo into the other. Fifty-two milliliters of bone marrow was aspirated from the iliac crests and concentrated in an automated centrifuge. The resulting BMAC was combined with platelet-poor plasma for an injection into the arthritic knee and was compared with a saline injection into the contralateral knee, thereby utilizing each patient as his or her own control. Safety outcomes, pain relief, and function as measured by Osteoarthritis Research Society International (OARSI) measures and the visual analog scale (VAS) score were tracked initially at 1 week, 3 months, and 6 months after the procedure.
Results:
There were no serious adverse events from the BMAC procedure. OARSI Intermittent and Constant Osteoarthritis Pain and VAS pain scores in both knees decreased significantly from baseline at 1 week, 3 months, and 6 months (P ≤ .019 for all). Pain relief, although dramatic, did not differ significantly between treated knees (P > .09 for all).
Conclusion:
Early results show that BMAC is safe to use and is a reliable and viable cellular product. Study patients experienced a similar relief of pain in both BMAC- and saline-treated arthritic knees. Further study is required to determine the mechanisms of action, duration of efficacy, optimal frequency of treatments, and regenerative potential.
Registration:
ClinicalTrials.gov record 12-004459.
These preliminary data from an ongoing first-in-human phase 1/2, open-label study provide proof-of-concept that pluripotent stem cell-derived pancreatic endoderm cells (PEC-01) engrafted in type 1 ...diabetes patients become islet cells releasing insulin in a physiologically regulated fashion. In this study of 17 subjects aged 22-57 with type 1 diabetes, PEC-01 cells were implanted subcutaneously in VC-02 macroencapsulation devices, allowing for direct vascularization of the cells. Engraftment and insulin expression were observed in 63% of VC-02 units explanted from subjects at 3–12 months post-implant. Six of 17 subjects (35.3%) demonstrated positive C-peptide as early as 6 months post-implant. Most reported adverse events were related to surgical implant or explant procedures (27.9%) or to side-effects of immunosuppression (33.7%). Initial data suggest that pluripotent stem cells, which can be propagated to the desired biomass and differentiated into pancreatic islet-like tissue, may offer a scalable, renewable alternative to pancreatic islet transplants.
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•Findings are shared for the first 17 participants in a phase 1/2 trial of VC-02•This investigational device was implanted into type 1 diabetes patients•VC-02 contains pluripotent stem cell-derived pancreatic endoderm cells•C-peptide levels and insulin expression correlate with engraftment in 63% of subjects
Shapiro et al. report preliminary proof-of-concept that in 17 people with type 1 diabetes, pancreatic endoderm cells in an investigational subcutaneous device (VC-02) achieved engraftment and insulin expression in 63% of units at 3–12 months post-implant. Pluripotent stem cells may be a scalable, renewable alternative to pancreatic islet transplants.
One of the most promising applications of liver normothermic machine perfusion (NMP) is the potential to directly assess graft viability and injury. In most NMP studies, perfusate transaminases are ...utilized as markers of graft injury. Our aim was to further elucidate the metabolism of transaminases by healthy porcine livers during NMP, specifically whether such livers could clear circuit perfusate transaminases.
A highly concentrated transaminase solution was prepared from homogenized liver, with an aspartate aminotransferase (AST) level of 107,427 U/L. Three livers in the treatment group were compared to three controls, during 48 hours of NMP. In the treatment group, the circuit perfusate was injected with the transaminase solution to artificially raise the AST level to a target of 7,500 U/L. Perfusate samples were taken at two-hour intervals and analyzed for biochemistry until NMP end. Graft oxygen consumption and vascular parameters were monitored.
Compared to controls, treated perfusions demonstrated abrupt elevations in transaminase levels (p>0.0001) and lactate dehydrogenase (LDH) (p>0.0001), which decreased over time, but never to control baseline. Liver function, as demonstrated by lactate clearance and oxygen consumption was not different between groups. The treatment group demonstrated a higher portal vein resistance (p = 0.0003), however hepatic artery resistance was similar. Treated livers had higher bile production overall (p<0.0001).
Addition of high levels of transaminases and LDH to a healthy porcine liver during ex situ perfusion results in progressive clearance of these enzymes, suggesting preserved liver metabolism. Such tolerance tests may provide valuable indicators of prospective graft function.
Context. There is no consensus on the amplitude of historical solar forcing. The estimated magnitude of the total solar irradiance (TSI) difference between the Maunder minimum and the present time ...ranges from 0.1 to 6 W m−2 making the simulation of the past and future climate uncertain. One reason for this disagreement is the applied evolution of the quiet Sun brightness in solar irradiance reconstruction models. This work addresses the role of the quiet Sun model choice and updated solar magnetic activity proxies on the solar forcing reconstruction. Aims. We aim to establish a plausible range for the solar irradiance variability on decadal to millennial timescales. Methods. The spectral solar irradiance (SSI) is calculated as a weighted sum of the contributions from sunspot umbra, sunspot penumbra, faculae, and quiet Sun, which are pre-calculated with the NLTE Spectral SYnthesis code (NESSY). We introduce activity belts of the contributions from sunspots and faculae and a new structure model for the quietest state of the Sun. We assume that the brightness of the quiet Sun varies in time proportionally to the secular (22-yr smoothed) variation of the solar modulation potential. Results. A new reconstruction of the TSI and SSI covering the period 6000 BCE - 2015 CE is presented. The model simulates solar irradiance variability during the satellite era well. The TSI change between the Maunder and recent minima ranges between 3.7 and 4.5 W m−2 depending on the applied solar modulation potential. The implementation of a new quietest Sun model reduces, by approximately a factor of two, the relative solar forcing compared to the largest previous estimation, while the application of an updated solar modulation potential increases the forcing difference between the Maunder minimum and the present by 25–40%.
Maternal obesity increases adult offspring risk for cardiovascular disease; however, the role of offspring adiposity in mediating this association remains poorly characterized.
To investigate the ...associations of maternal pre-pregnant body mass index (maternal BMI) and gestational weight gain (GWG) with neonatal cardiometabolic markers independent of fetal growth and neonatal adiposity.
A total of 753 maternal-infant pairs from the Healthy Start study, a large multiethnic pre-birth observational cohort were used. Neonatal cardiometabolic markers included cord blood glucose, insulin, glucose-to-insulin ratio (Glu/Ins), total and high-density lipoprotein cholesterol (HDL-c), triglycerides, free fatty acids and leptin. Maternal BMI was abstracted from medical records or self-reported. GWG was calculated as the difference between the first pre-pregnant weight and the last weight measurement before delivery. Neonatal adiposity (percent fat mass) was measured within 72 h of delivery using whole-body air-displacement plethysmography.
In covariate adjusted models, maternal BMI was positively associated with cord blood insulin (P=0.01) and leptin (P<0.001) levels, and inversely associated with cord blood HDL-c (P=0.05) and Glu/Ins (P=0.003). Adjustment for fetal growth or neonatal adiposity attenuated the effect of maternal BMI on neonatal insulin, rendering the association nonsignificant. However, maternal BMI remained associated with higher leptin (P<0.0011), lower HDL-c (P=0.02) and Glu/Ins (P=0.05), independent of neonatal adiposity. GWG was positively associated with neonatal insulin (P=0.02), glucose (P=0.03) and leptin levels (P<0.001) and negatively associated with Glu/Ins (P=0.006). After adjusting for neonatal adiposity, GWG remained associated with higher neonatal glucose (P=0.02) and leptin levels (P=0.02) and lower Glu/Ins (P=0.048).
Maternal weight prior and/or during pregnancy is associated with neonatal cardiometabolic makers including leptin, glucose and HDL-c at delivery, independent of neonatal adiposity. Our results suggest that intrauterine exposure to maternal obesity influences metabolic processes beyond fetal growth and fat accretion.
Normothermic machine perfusion (NMP) has emerged as a valuable tool in the preservation of liver allografts before transplantation. Randomized trials have shown that replacing static cold storage ...(SCS) with NMP reduces allograft injury and improves graft utilization. The University of Alberta’s liver transplant program was one of the early adopters of NMP in North America. Herein, we describe our 7-year experience applying NMP to extend preservation time in liver transplantation using a “back-to-base” approach. From 2015 to 2021, 79 livers were transplanted following NMP, compared with 386 after SCS only. NMP livers were preserved for a median time of minutes compared with minutes in the SCS cohort (P < .0001). Despite this, we observed significantly improved 30-day graft survival (P = .030), although there were no differences in long-term patient survival, major complications, or biliary or vascular complications. We also found that although SCS time was strongly associated with increased graft failure at 1 year in the SCS cohort (P = .006), there was no such association among NMP livers (P = .171). Our experience suggests that NMP can safely extend the total preservation time of liver allografts without increasing complications.
Layered oxides widely used as lithium-ion battery electrodes are designed to be cycled under conditions that avoid phase transitions. Although the desired single-phase composition ranges are well ...established near equilibrium, operando diffraction studies on many-particle porous electrodes have suggested phase separation during delithiation. Notably, the separation is not always observed, and never during lithiation. These anomalies have been attributed to irreversible processes during the first delithiation or reversible concentration-dependent diffusion. However, these explanations are not consistent with all experimental observations such as rate and path dependencies and particle-by-particle lithium concentration changes. Here, we show that the apparent phase separation is a dynamical artefact occurring in a many-particle system driven by autocatalytic electrochemical reactions, that is, an interfacial exchange current that increases with the extent of delithiation. We experimentally validate this population-dynamics model using the single-phase material Li
(Ni
Mn
Co
)O
(0.5 < x < 1) and demonstrate generality with other transition-metal compositions. Operando diffraction and nanoscale oxidation-state mapping unambiguously prove that this fictitious phase separation is a repeatable non-equilibrium effect. We quantitatively confirm the theory with multiple-datastream-driven model extraction. More generally, our study experimentally demonstrates the control of ensemble stability by electro-autocatalysis, highlighting the importance of population dynamics in battery electrodes (even non-phase-separating ones).
The maximum possible earthquake related to gas production in Western Europe's largest gas field, Groningen, Netherlands, is an urgent practical question. Here we show how to distinguish between ...induced and triggered tectonic earthquakes. We estimate the maximum possible induced magnitude in the Groningen gas field to be around M
= 4. We extend the concept of the seismogenic index to gas-production, and calculate the worst-case probability of triggering a larger-magnitude tectonic earthquake in a continuum. The probability of a M
5.5 earthquake at Groningen is significantly higher than at Pohang Geothermal System (South Korea), where a M
5.5 earthquake was actually triggered. Due to a long history of production in Groningen, our model estimates that strong earthquakes (M
≥ 4) must have occurred there several times, in disagreement with the observations. This indicates that the Groningen gas field is inherently stable and the physical conditions to trigger large tectonic earthquakes likely do not exist.
Islet transplantation offers an effective treatment for selected people with type 1 diabetes and intractable hypoglycaemia. Long-term experience, however, remains limited. We report outcomes from a ...single-centre cohort up to 20 years after islet transplantation.
This cohort study included patients older than 18 years with type 1 diabetes undergoing allogeneic islet transplantation between March 11, 1999, and Oct 1, 2019, at the University of Alberta Hospital (Edmonton, AB, Canada). Patients who underwent islet-after-kidney transplantation and islet transplantation alone or islet transplantation before whole-pancreas transplantation (follow-up was censored at the time of whole-pancreas transplantation) were included. Patient survival, graft survival (fasting plasma C-peptide >0·1 nmol/L), insulin independence, glycaemic control, and adverse events are reported. To identify factors associated with prolonged graft survival, recipients with sustained graft survival (≥90% of patient follow-up duration) were compared with those who had non-sustained graft survival (<90% of follow-up duration). Multivariate binary logistic regression analyses were done to determine predictors of sustained graft survival.
Between March 11, 1999, and Oct 1, 2019, 255 patients underwent islet transplantation and were included in the analyses (149 58% were female and 218 85% were White). Over a median follow-up of 7·4 years (IQR 4·4-12·2), 230 (90%) patients survived. Median graft survival was 5·9 years (IQR 3·0-9·5), and graft failure occurred in 91 (36%) patients. 178 (70%) recipients had sustained graft survival, and 77 (30%) had non-sustained graft survival. At baseline, compared with patients with non-sustained graft survival, those with sustained graft survival had longer median type 1 diabetes duration (33·5 years IQR 24·3-41·7 vs 26·2 years 17·0-35·5; p=0·0003), median older age (49·4 years 43·5-56·1 vs 44·2 years 35·4-54·2; p=0·0011), and lower median insulin requirements (0·53 units/kg per day 0·45-0·67 vs 0·59 units/kg per day 0·48-0·70; p=0·032), but median HbA
concentrations were similar (8·2% 7·5-9·0 vs 8·5% 7·8-9·2; p=0·23). 201 (79%) recipients had insulin independence, with a Kaplan-Meier estimate of 61% (95% CI 54-67) at 1 year, 32% (25-39) at 5 years, 20% (14-27) at 10 years, 11% (6-18) at 15 years, and 8% (2-17) at 20 years. Patients with sustained graft survival had significantly higher rates of insulin independence (160 90% of 178 vs 41 53% of 77; p<0·0001) and sustained improvements in glycaemic control mixed-main-effects model group effect, p<0·0001) compared with those with non-sustained graft survival. Multivariate analyses identified the combined use of anakinra plus etanercept (adjusted odds ratio 7·5 95% CI 2·7-21·0, p<0·0001) and the BETA-2 score of 15 or higher (4·1 1·5-11·4, p=0·0066) as factors associated with sustained graft survival. In recipients with sustained graft survival, the incidence of procedural complications was lower (23 5% of 443 infusions vs 17 10% of 167 infusions; p=0·027), whereas the incidence of cancer was higher (29 of 16% of 178 vs four 5% of 77; p=0·015) than in those with non-sustained graft survival; most were skin cancers (22 67% of 33). End-stage renal disease and severe infections were similar between groups.
We present the largest single-centre cohort study of long-term outcomes following islet transplantation. Although some limitations with our study remain, such as the retrospective component, a relatively small sample size, and the absence of non-transplant controls, we found that the combined use of anakinra plus etanercept and the BETA-2 score were associated with improved outcomes, and therefore these factors could inform clinical practice.
None.
The kinetics and uniformity of ion insertion reactions at the solid-liquid interface govern the rate capability and lifetime, respectively, of electrochemical devices such as Li-ion batteries. Using ...an operando x-ray microscopy platform that maps the dynamics of the Li composition and insertion rate in LixFePO₄, we found that nanoscale spatial variations in rate and in composition control the lithiation pathway at the subparticle length scale. Specifically, spatial variations in the insertion rate constant lead to the formation of nonuniform domains, and the composition dependence of the rate constant amplifies nonuniformities during delithiation but suppresses them during lithiation, and moreover stabilizes the solid solution during lithiation. This coupling of lithium composition and surface reaction rates controls the kinetics and uniformity during electrochemical ion insertion.
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