Interleukin-17A (IL-17A) is elaborated by the T helper 17 (T(H)17) subset of T(H) cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced ...arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A-producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.
Abstract
Ghana has retained a substantial area of tropical forests in an extensive network of protected reserves. These forests are impacted by land uses such as logging, mining, and agriculture as ...well as wildfires. We studied forest disturbance and recovery from 2013 to 2020 using annual maps of forest cover derived from Landsat imagery. Fire-associated disturbance was distinguished using VIIRS active fire data. We used boosted regression trees to model disturbances in closed and open forests as a function of climate variability, human accessibility, and landscape structure. A total of 3562 km
2
of forest reserves were disturbed, of which 17% (615 km
2
) were fire disturbances and 83% (2946 km
2
) were non-fire disturbances. Of the total disturbed area, 68% was degradation (change from closed to open forest), 28% was open forest loss, and only 4% was closed forest loss. Over the same period, 2702 km
2
of forest reserves recovered, with 1948 km
2
of these recovering to closed-canopy forests. Fire disturbances were strongly associated with precipitation anomalies and occurred mostly in drier years, whereas non-fire disturbances had weaker relationships with precipitation. Disturbances in closed forests occurred in landscapes where closed forest cover was already low. In contrast, disturbances in open forests were most common in locations with intermediate levels of population pressure from nearby cities and proximity to non-forest land cover. The results support the idea that forest disturbance in Ghana is a multi-stage process involving degradation of closed forests followed by loss of the resulting open forests. Although non-fire disturbance rates are consistent from year to year, sharp increases in fire disturbance occur in drought years. Locations with the highest disturbance risk are associated with measurable indicators of climate, human pressure, and fragmentation, which can be used to identify these areas for conservation and forest restoration activities.
In humans, Streptococcus agalactiae or group B streptococcus (GBS) is a frequent coloniser of the rectovaginal tract, a major cause of neonatal infectious disease and an emerging cause of disease in ...non-pregnant adults. In addition, Streptococcus agalactiae causes invasive disease in fish, compromising food security and posing a zoonotic hazard. We studied the molecular epidemiology of S. agalactiae in fish and other aquatic species to assess potential for pathogen transmission between aquatic species and humans.
Isolates from fish (n = 26), seals (n = 6), a dolphin and a frog were characterized by pulsed-field gel electrophoresis, multilocus sequence typing and standardized 3-set genotyping, i.e. molecular serotyping and profiling of surface protein genes and mobile genetic elements.
Four subpopulations of S. agalactiae were identified among aquatic isolates. Sequence type (ST) 283 serotype III-4 and its novel single locus variant ST491 were detected in fish from Southeast Asia and shared a 3-set genotype identical to that of an emerging ST283 clone associated with invasive disease of adult humans in Asia. The human pathogenic strain ST7 serotype Ia was also detected in fish from Asia. ST23 serotype Ia, a subpopulation that is normally associated with human carriage, was found in all grey seals, suggesting that human effluent may contribute to microbial pollution of surface water and exposure of sea mammals to human pathogens. The final subpopulation consisted of non-haemolytic ST260 and ST261 serotype Ib isolates, which belong to a fish-associated clonal complex that has never been reported from humans.
The apparent association of the four subpopulations of S. agalactiae with specific groups of host species suggests that some strains of aquatic S. agalactiae may present a zoonotic or anthroponotic hazard. Furthermore, it provides a rational framework for exploration of pathogenesis and host-associated genome content of S. agalactiae strains.
Electric-vehicle grid integration has the potential to stress distribution network equipment and increase peak consumption, unless properly managed. In this paper, we use dynamic programming to ...develop a decision support algorithm and market participation policy for a load aggregator (LA) managing the charging of plug-in electric vehicles (PEVs) connecting at the same distribution network feeder. The LA submits inflexible and flexible bids to a liberalized hour-ahead power market, while monitoring localized feeder and PEV rate constraints. Flexible bids, which include a bid price or utility, can be cleared as regulation service, cleared as energy, or rejected by the market operator. These market events are probabilistically included within the modeling framework. A case study, based on New York independent system operator data, found that the market participation policy may reduce daily electricity costs for PEVs significantly more than is expected through forecasted electricity-price-based scheduling.
Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed ...B7-H3-specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation.
This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF. This article is highlighted in the In This Issue feature, p. 1.
Structural plasticity of enzymes dictates their function. Yet, our ability to rationally remodel enzyme conformational landscapes to tailor catalytic properties remains limited. Here, we report a ...computational procedure for tuning conformational landscapes that is based on multistate design of hinge-mediated domain motions. Using this method, we redesign the conformational landscape of a natural aminotransferase to preferentially stabilize a less populated but reactive conformation and thereby increase catalytic efficiency with a non-native substrate, resulting in altered substrate selectivity. Steady-state kinetics of designed variants reveals activity increases with the non-native substrate of approximately 100-fold and selectivity switches of up to 1900-fold. Structural analyses by room-temperature X-ray crystallography and multitemperature nuclear magnetic resonance spectroscopy confirm that conformational equilibria favor the target conformation. Our computational approach opens the door to targeted alterations of conformational states and equilibria, which should facilitate the design of biocatalysts with customized activity and selectivity.
To evaluate the trends and hospital variation in the use of pharmacologic restraint among pediatric mental health visits in the emergency department (ED).
We examined ED visits with a mental health ...diagnosis in patients aged 3-21 years at children's hospital EDs from 2009 to 2019. We calculated the frequency of pharmacologic restraint use and determined visit characteristics associated with restraint use. We calculated cumulative percent change for visits with restraints and for all mental health visits. We used logistic regression to test trends over time and evaluate hospital variation in the frequency of restraint use.
We identified 389 885 mental health ED visits (54.9% female, median age 14.3 years) and 13 643 (3.5%) visits with pharmacologic restraint use. Characteristics associated with pharmacologic restraint use were late adolescent age (18-21 years), male sex, Black race, non-Latino ethnicity, public insurance, and admission to the hospital (P < .001). During the study period, both mental health ED visits increased by 268% and mental health ED visits with pharmacologic restraint use increased by 370%. The rate of pharmacologic restraint in this patient population remained constant. Hospital use of pharmacologic restraint for mental health visits varied significantly across hospitals (1.6%-11.8%, P < .001).
Pediatric mental health ED visits with and without pharmacologic restraint are increasing over time. In addition, the overall number of pharmacologic restraint use has increased threefold. Significant hospital variation in pharmacologic restraint use signifies an opportunity for standardization of care and restraint reduction.
By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants ...in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.
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