In this work, we couple theoretical and experimental approaches to understand and reduce the losses of wide bandgap Br-rich perovskite pin devices at open-circuit voltage (V
) and short-circuit ...current (J
) conditions. A mismatch between the internal quasi-Fermi level splitting (QFLS) and the external V
is detrimental for these devices. We demonstrate that modifying the perovskite top-surface with guanidinium-Br and imidazolium-Br forms a low-dimensional perovskite phase at the n-interface, suppressing the QFLS-V
mismatch, and boosting the V
. Concurrently, the use of an ionic interlayer or a self-assembled monolayer at the p-interface reduces the inferred field screening induced by mobile ions at J
, promoting charge extraction and raising the J
. The combination of the n- and p-type optimizations allows us to approach the thermodynamic potential of the perovskite absorber layer, resulting in 1 cm
devices with performance parameters of V
s up to 1.29 V, fill factors above 80% and J
s up to 17 mA/cm
, in addition to a thermal stability T
lifetime of more than 3500 h at 85 °C.
Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely ...immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue.
We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (10
or 10
plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis.
Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes.
Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically "cold" tumors to "hot." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.).
Children with type 1 diabetes (T1D) experience an increased risk of fracture, which may be related to altered bone development. We aimed to assess differences in bone, muscle and physical activity ...(PA), and explore if better muscle and PA measures would mitigate bone differences between children and adolescents with T1D and typically developing peers (TDP). We matched 56 children and adolescents with T1D (mean age 11.9 yrs) and 56 TDP (11.5 yrs) by sex and maturity from 171 participants with T1D and 66 TDP (6-17 yrs). We assessed the distal radius and tibia with high-resolution peripheral quantitative computed tomography (HR-pQCT), and the radius and tibia shaft bone and muscle with pQCT. We also measured muscle function from force-related measures in neuromuscular performance tests (push-up, grip test, countermovement and long jump). We compared PA based on questionnaire scores and accelerometers between groups. Bone, muscle, and neuromuscular performance measures were compared using MANOVA. We used mediation to explore the role of PA and muscle in bone differences. Children and adolescents with T1D had 6–10 % lower trabecular density, bone volume fraction, thickness and number at both distal radius and tibia, and 11 % higher trabecular separation at the distal radius than TDP. They also had 3–16 % higher cortical and tissue mineral density, and cortical thickness at the distal radius, 5–7 % higher cortical density and 1–3 % higher muscle density at both shaft sites compared to TDP. PA mediated the between-group difference in trabecular number (indirect effect −0.04) at the distal radius. Children and adolescents with T1D had lower trabecular bone density and deficits in trabecular micro-architecture, but higher cortical bone density and thickness at the radius and tibia compared to TDP. They engaged in less PA but had comparable muscle measures to those of TDP. PA participation may assist in mitigating deficit in trabecular number observed in children and adolescents with T1D.
•Children with T1D had lower trabecular density, micro-architecture at distal sites.•Higher cortical density and thickness at distal radius and shaft sites in T1D•More physical activity may mitigate trabecular bone difference in T1D.•Prospective, advanced imaging data of bone development in children with T1D needed.
Deficits in bone mineral and weaker bone structure in children with type 1 diabetes (T1D) may contribute to a lifelong risk of fracture. However, there is no meta-analysis comparing bone properties ...beyond density between children with T1D and typically developing children (TDC). This meta-analysis aimed to assess differences and related factors in bone mineral content (BMC), density, area, micro-architecture and estimated strength between children with T1D and TDC. We systematically searched MEDLINE, Embase, CINAHL, Web of Science, Scopus, Cochrane Library databases, and included 36 in the meta-analysis (2222 children and youth with T1D, 2316 TDC; mean age ≤18 yrs., range 1–24). We estimated standardized mean differences (SMD) using random-effects models and explored the role of age, body size, sex ratio, disease duration, hemoglobin A1c in relation to BMC and areal density (aBMD) SMD using meta-regressions. Children and youth with T1D had lower total body BMC (SMD: −0.21, 95% CI: −0.37 to −0.05), aBMD (−0.30, −0.50 to −0.11); lumbar spine BMC (−0.17, −0.28 to −0.06), aBMD (−0.20, −0.32 to −0.08), bone mineral apparent density (−0.30, −0.48 to −0.13); femoral neck aBMD (−0.21, −0.33 to −0.09); distal radius and tibia trabecular density (−0.38, −0.64 to −0.12 and −0.35, −0.51 to −0.18, respectively) and bone volume fraction (−0.33, −0.56 to −0.09 and −0.37, −0.60 to −0.14, respectively); distal tibia trabecular thickness (−0.41, −0.67 to −0.16); and tibia shaft cortical content (−0.33, −0.56 to −0.10). Advanced age was associated with larger SMD in total body BMC (−0.13, −0.21 to −0.04) and aBMD (−0.09; −0.17 to −0.01) and longer disease duration with larger SMD in total body aBMD (−0.14; −0.24 to −0.04). Children and youth with T1D have lower BMC, aBMD and deficits in trabecular density and micro-architecture. Deficits in BMC and aBMD appeared to increase with age and disease duration. Bone deficits may contribute to fracture risk and require attention in diabetes research and care.
PROSPERO (CRD42020200819).
•First meta-analysis of BMC and micro-architectural deficits in children with T1D•Meta-regressions indicated greater deficits in total body BMC and aBMD with age.•Deficits in trabecular bone thickness and density were pronounced in T1D.•Prospective, advanced imaging data of bone development in children with T1D needed
Mutualisms are important ecological interactions that underpin much of the world's biodiversity. Predation risk has been shown to regulate mutualism dynamics in species‐specific case studies; ...however, we lack studies which investigate whether predation can also explain broader patterns of mutualism evolution. We report that fish‐anemone mutualisms have evolved on at least 55 occasions across 16 fish families over the past 60 million years and that adult body size is associated with the ontogenetic stage of anemone mutualisms: larger‐bodied species partner with anemones as juveniles, while smaller‐bodied species partner with anemones throughout their lives. Field and laboratory studies show that predators target smaller prey, that smaller fishes associate more with anemones, and that these relationships confer protection to small fishes. Our results indicate that predation is likely driving the recurrent convergent evolution of fish‐anemone mutualisms and suggest that similar ecological processes may have selected convergence in interspecies interactions in other animal clades.
Chronic lymphocytic leukemia (CLL) remains incurable despite advances in therapy. In this study, we characterize the effect of nicotinamide phosphoribosyltransferase (NAMPT) inhibition by FK866 in ...primary CLL cells from patients with various clinical prognostic markers.
CLL cells were treated with FK866 to assess viability by Annexin V/PI staining. Functional analysis of FK866 included time- and concentration-dependent evaluation of cellular NAD, ATP, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and apoptotic signaling. Chemosensitization potential by FK866 to fludarabine was also assessed. Prognostic markers were correlated with drug response.
FK866 induced CLL cell death by depleting cellular NAD content by day 1, followed by a drop in ATP on day 2. We observed loss of MMP, ROS increase, and induction of apoptotic signaling at day 3. On-target activity of FK866 was confirmed by NAD-mediated rescue of NAD and ATP loss, apoptotic signaling, and viability. The response to FK866 was independent of most prognostic markers. Higher doses were required with short lymphocyte doubling time and positive CD38 status, whereas CLL cells resistant to fludarabine in vitro and from patients with del17p13.1 were equally sensitive to FK866. FK866 did not upregulate the p53-target p21, nor did the p53 activator Nutlin improve FK866-mediated cell death. Furthermore, fludarabine and FK866 were synergistic at clinically relevant concentrations.
NAMPT inhibition by FK866 may be a potential treatment for CLL, including patients with del17p13.1 or other high-risk features. FK866 may complement standard agents to enhance their efficacy and/or allow dose reduction for improved tolerability.
How Is Physician Work Valued? Jacobs, Jeffrey P; Lahey, Stephen J; Nichols, Francis C ...
The Annals of thoracic surgery,
02/2017, Volume:
103, Issue:
2
Journal Article
Peer reviewed
Open access
Strategies to value physician work continue to evolve. The Society of Thoracic Surgeons and The Society of Thoracic Surgeons National Database have an increasingly important role in this evolution. ...An understanding of the Current Procedural Terminology (CPT) system (American Medical Association AMA, Chicago, IL) and the Relative Value Scale Update Committee (RUC) is necessary to comprehend how physician work is valued. In 1965, with the dawn of increasingly complex medical care, immense innovation, and the rollout of Medicare, the need for a common language describing medical services and procedures was recognized as being of critical importance. In 1966, the AMA, in cooperation with multiple major medical specialty societies, developed the CPT system, which is a coding system for the description of medical procedures and medical services. The RUC was created by the AMA in response to the passage of the Omnibus Budget Reconciliation Act of 1989, legislation of the United States of America Federal government that mandated that the Centers for Medicare & Medicaid Services adopt a relative value methodology for Medicare physician payment. The role of the RUC is to develop relative value recommendations for the Centers for Medicare & Medicaid Services. These recommendations include relative value recommendations for new procedures or services and also updates to relative value recommendations for previously valued procedures or services. These recommendations pertain to all physician work delivered to Medicare beneficiaries and propose relative values for all physician services, including updates to those based on the original resource-based relative value scale developed by Hsaio and colleagues. In so doing, widely differing work and services provided can be reviewed and comparisons of their relative value (to each other) can be established. The resource-based relative value scale assigns value to physician services using relative value units (RVUs), which consist of three components: work RVU, practice expense RVU, and malpractice RVU, also known as professional liability insurance RVU. The Centers for Medicare & Medicaid Services retains the final decision-making authority on the RVUs associated with each procedure or service. The purpose of this article is to discuss the role that the CPT codes and the RUC play in the valuation of physician work and to provide an example of how the methodology for valuation of physician work continues to evolve.
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