Clinical islet transplantation effectively restores euglycemia and corrects glycosylated hemoglobin in labile type 1 diabetes mellitus (T1DM). Despite marked improvements in islet transplantation ...outcomes, acute islet cell death remains a substantial obstacle that compromises long-term engraftment outcomes. Multiple organ donors are routinely required to achieve insulin independence. Therapeutic agents that ameliorate cell death and/or control injury-related inflammatory cascades offer potential to improve islet transplant success. Apoptotic cell death has been identified as a major contributor to cellular demise and therapeutic strategies that subvert initiation and consequences of apoptotic cell death have shown promise in pre-clinical models. Indeed, in numerous pathologies and diseases apoptosis has been the most extensively described form of regulated cell death. However, recent identification of novel, alternative regulated cell death pathways in other disease states and solid organ transplantation suggest that these additional pathways may also have substantial relevance in islet transplantation. These regulated, non-apoptotic cell death pathways exhibit distinct biochemical characteristics but have yet to be fully characterized within islet transplantation. We review herein the various regulated cell death pathways and highlight their relative potential contributions to islet viability, engraftment failure and islet dysfunction.
Screening for tuberculosis (TB) disease aims to improve early TB case detection. The ultimate goal is to improve outcomes for people with TB and to reduce Mycobacterium tuberculosis transmission in ...the community through improved case detection, reduction in diagnostic delays and early treatment. Before screening programmes are recommended, evidence is needed of individual and/or community-level benefits.
We conducted a systematic review of the literature to assess the evidence that screening for TB disease 1) initially increases the number of TB cases initiated on anti-tuberculosis treatment, 2) identifies cases earlier in the course of disease, 3) reduces mortality and morbidity, and 4) impacts on TB epidemiology.
A total of 28 798 publications were identified by the search strategy: 27 087 were excluded on initial screening and 1749 on full text review, leaving 62 publications that addressed at least one of the study questions. Screening increases the number of cases found in the short term. In many settings, more than half of the prevalent TB cases in the community remain undiagnosed. Screening tends to find cases earlier and with less severe disease, but this may be attributed to case-finding studies using more sensitive diagnostic methods than routine programmes. Treatment outcomes among people identified through screening are similar to outcomes among those identified through passive case finding. Current studies provide insufficient evidence to show that active screening for TB disease impacts on TB epidemiology.
Individual and community-level benefits from active screening for TB disease remain uncertain. So far, the benefits of earlier diagnosis on patient outcomes and transmission have not been established.
After extensive experimentation, outcomes of a first clinical normothermic machine perfusion (NMP) liver trial in the United Kingdom demonstrated feasibility and clear safety, with improved liver ...function compared with standard static cold storage (SCS). We present a preliminary single‐center North American experience using identical NMP technology. Ten donor liver grafts were procured, four (40%) from donation after circulatory death (DCD), of which nine were transplanted. One liver did not proceed because of a technical failure with portal cannulation and was discarded. Transplanted NMP grafts were matched 1:3 with transplanted SCS livers. Median NMP was 11.5 h (range 3.3–22.5 h) with one DCD liver perfused for 22.5 h. All transplanted livers functioned, and serum transaminases, bilirubin, international normalized ratio, and lactate levels corrected in NMP recipients similarly to controls. Graft survival at 30 days (primary outcome) was not statistically different between groups on an intent‐to‐treat basis (p = 0.25). Intensive care and hospital stays were significantly more prolonged in the NMP group. This preliminary experience demonstrates feasibility as well as potential technical risks of NMP in a North American setting and highlights a need for larger, randomized studies.
This paper describes a preliminary Canadian single‐center experience with clinical ex vivo normothermic liver perfusion and transplantation. See the video at amjtransplant.com/videos.
Transition metal (oxy)hydroxides are promising electrocatalysts for the oxygen evolution reaction
. The properties of these materials evolve dynamically and heterogeneously
with applied voltage ...through ion insertion redox reactions, converting materials that are inactive under open circuit conditions into active electrocatalysts during operation
. The catalytic state is thus inherently far from equilibrium, which complicates its direct observation. Here, using a suite of correlative operando scanning probe and X-ray microscopy techniques, we establish a link between the oxygen evolution activity and the local operational chemical, physical and electronic nanoscale structure of single-crystalline β-Co(OH)
platelet particles. At pre-catalytic voltages, the particles swell to form an α-CoO
H
0.5H
O-like structure-produced through hydroxide intercalation-in which the oxidation state of cobalt is +2.5. Upon increasing the voltage to drive oxygen evolution, interlayer water and protons de-intercalate to form contracted β-CoOOH particles that contain Co
species. Although these transformations manifest heterogeneously through the bulk of the particles, the electrochemical current is primarily restricted to their edge facets. The observed Tafel behaviour is correlated with the local concentration of Co
at these reactive edge sites, demonstrating the link between bulk ion-insertion and surface catalytic activity.
In this paper we consider optimization problems where the objective function is given in a form of the expectation. A basic difficulty of solving such stochastic optimization problems is that the ...involved multidimensional integrals (expectations) cannot be computed with high accuracy. The aim of this paper is to compare two computational approaches based on Monte Carlo sampling techniques, namely, the stochastic approximation (SA) and the sample average approximation (SAA) methods. Both approaches, the SA and SAA methods, have a long history. Current opinion is that the SAA method can efficiently use a specific (say, linear) structure of the considered problem, while the SA approach is a crude subgradient method, which often performs poorly in practice. We intend to demonstrate that a properly modified SA approach can be competitive and even significantly outperform the SAA method for a certain class of convex stochastic problems. We extend the analysis to the case of convex-concave stochastic saddle point problems and present (in our opinion highly encouraging) results of numerical experiments.
The paucity of human donors limits broadened application of β-cell replacement therapy. Insulin-producing cells derived from human embryonic stem cells (hESCs) have recently been investigated ...clinically as a feasible surrogate to primary tissue. Herein, we examine the long-term efficacy of hESC-derived pancreatic endoderm cells (PECs) to maintain normoglycemia posttransplant and characterize the phenotype of the PEC grafts. Mice with chemically induced diabetes were transplanted with PECs into the subcutaneous device-less site. Transplant function was assessed through nonfasting blood glucose measurements, intraperitoneal glucose tolerance testing (IPGTT), and human C-peptide secretion for 517 days. Explanted grafts were assessed for ex vivo function and immunohistochemically. All PEC recipients (
= 8) maintained normoglycemia until graft retrieval. IPGTTs at 365 and 517 days posttransplant did not differ (
> 0.05), however, both demonstrated superior glucose clearance compared with nondiabetic and transplant controls (
< 0.001). Serum C-peptide levels demonstrated significant glucose responsiveness (fasted vs. stimulated) (
< 0.01). Small intragraft cysts were palpable in all mice, which resolved but recurred after aspiration. Cysts showed monomorphic neuroendocrine proliferation and lined by ductal epithelium. Explanted grafts demonstrated similar insulin secretory capacity as human islets and stained positively for endocrine cells. Our results demonstrate the ability of PECs to differentiate in vivo and restore glycemic control while confirming minimal proliferation and absence of neoplastic change within the grafts during the time evaluated.
Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in ...preventing SHEs in 50-80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment.
This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant.
The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients.
Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.
Over 160 therapeutic and
diagnostic monoclonal antibodies have been approved by the US FDA since the first monoclonal antibody, muromonab, was approved in 1986. Approximately 42% of these approvals ...were for the treatment or
diagnosis of oncology indications, although some products are no longer marketed. This review will look at the history of monoclonal antibody development and approvals, discuss current antibody-based modalities, regulatory considerations for engineering approaches, critical quality attributes for different modalities, immunogenicity of mAbs across oncology products, and the future directions for development of therapeutic and diagnostic monoclonal antibody-based products.
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