The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety ...assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2×2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis. Sensitivity was 48% with a 43% positive predictive value (PPV). The nonhuman primate had the strongest performance in predicting adverse effects, especially for gastrointestinal and nervous system categories. When the same target organ was identified in both the rodent and nonrodent, the PPV increased. Specificity was 84% with an 86% negative predictive value (NPV). The beagle dog had the strongest performance in predicting an absence of clinical adverse effects. If no target organ toxicity was observed in either test species, the NPV increased. While nonclinical studies can demonstrate great value in the PPV for certain species and organ categories, the NPV was the stronger predictive performance measure across test species and target organs indicating that an absence of toxicity in animal studies strongly predicts a similar outcome in the clinic. These results support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials and provide context for emerging alternate models.
•Translational database created to determine animal to human safety concordance.•182 molecules with animal and clinical data; concordance parameters determined•Positive predictive value of 43%; Negative predictive value of 86%•Absence of toxicity in animal study strongly predicts similar outcome in the clinic.•Database supports animal testing to ensure human safety in the clinic.
BACKGROUND: Consumption of 3 g oat β-glucan/d is considered sufficient to lower serum LDL cholesterol, but some studies have shown no effect. LDL cholesterol lowering by oat β-glucan may depend on ...viscosity, which is controlled by the molecular weight (MW) and amount of oat β-glucan solubilized in the intestine (C). OBJECTIVES: Our 2 primary objectives were to determine whether consumption of 3 g high-MW oat β-glucan/d would reduce LDL cholesterol and whether LDL cholesterol lowering was related to the log(MW x C) of oat β-glucan. DESIGN: In a double-blind, parallel-design, multicenter clinical trial, subjects with LDL cholesterol ≥3.0 and less-than or equal to5.0 mmol/L (n = 786 screened, n = 400 ineligible, n = 19 refused, n = 367 enrolled, and n = 345 completed) were randomly assigned to receive cereal containing wheat fiber (n = 87) or 3 g high-MW (2,210,000 g/mol, n = 86), 4 g medium-MW (850,000 g/mol, n = 67), 3 g medium-MW (530,000 g/mol, n = 64), or 4 g low-MW (210,000 g/mol, n = 63) oat β-glucan/d (divided doses, twice daily) for 4 wk. RESULTS: LDL cholesterol was significantly less with 3 g high-MW, 4 g medium-MW, and 3 g medium-MW oat β-glucan cereals than with the wheat-fiber cereal by 0.21 (5.5%; 95% CI: -0.11, -0.30; P = 0.002), 0.26 (6.5%; 95% CI: -0.14, -0.37; P = 0.0007), and 0.19 (4.7%; 95% CI: -0.08, -0.30; P = 0.01) mmol/L, respectively. However, the effect of 4 g low-MW oat β-glucan/d (0.10 mmol/L) was not significant (2.3%; 95% CI: 0.02, -0.20). By analysis of covariance, log(MW x C) was a significant determinant of LDL cholesterol (P = 0.003). Treatment effects were not significantly influenced by age, sex, study center, or baseline LDL cholesterol. CONCLUSIONS: The physicochemical properties of oat β-glucan should be considered when assessing the cholesterol-lowering ability of oat-containing products; an extruded breakfast cereal containing 3 g oat β-glucan/d with a high-MW (2,210,000 g/mol) or a medium-MW (530,000 g/mol) lowered LDL cholesterol similarly by almost equal to0.2 mmol/L (5%), but efficacy was reduced by 50% when MW was reduced to 210,000 g/mol. This trial was registered at www.clinicaltrials.gov as NCT00981981.
Childhood mortality remains high in sub-Saharan Africa. In this cluster-randomized, placebo-controlled trial, mortality among children younger than 5 years of age was lower among those who received ...azithromycin than among those who received placebo.
There is an increasing need to apply rigorous model-order-reduction techniques in the analysis of large-scale networks of inverter-based distributed generation resources due to the limitations of ...existing simulation tools. Various coherency-based aggregation techniques have long been used to construct reduced-order dynamic models of large-scale synchronous machine (SM) networks. Such techniques have the advantage of preserving the nonlinear nature of the dynamic model throughout the order-reduction process, enabling the efficient and accurate analysis of large-scale network dynamics during large disturbances such as fault events. This paper proposes the application of a rigorous coherency-based aggregation technique to the analysis of large-scale networks of grid-forming droop-controlled inverters. A rapid and powerful generalized eigenvalue perturbation technique for coherency identification, previously only applied to SM networks, is adapted to grid-forming droop-controlled inverter networks. The resulting reduced-order models are physically insightful and are capable of accurately reproducing the system response in the aftermath of large disturbances. For some networks, a rigorously-derived condition of coherency can be difficult to achieve, given the expected range of L-C-L filter impedances. To remedy this limitation, the potential for high-bandwidth inverter control to enforce the conditions that allow for coherency of droop-controlled inverters has been investigated and confirmed using a controller hardware-in-the loop testbed. Using this approach, the use of simple nonlinear aggregate inverter models to accurately model large sections of the inverter network can be more rigorously justified.
Abstract
Penguins lost the ability to fly more than 60 million years ago, subsequently evolving a hyper-specialized marine body plan. Within the framework of a genome-scale, fossil-inclusive ...phylogeny, we identify key geological events that shaped penguin diversification and genomic signatures consistent with widespread refugia/recolonization during major climate oscillations. We further identify a suite of genes potentially underpinning adaptations related to thermoregulation, oxygenation, diving, vision, diet, immunity and body size, which might have facilitated their remarkable secondary transition to an aquatic ecology. Our analyses indicate that penguins and their sister group (Procellariiformes) have the lowest evolutionary rates yet detected in birds. Together, these findings help improve our understanding of how penguins have transitioned to the marine environment, successfully colonizing some of the most extreme environments on Earth.
Autoimmune pancreatitis (AIP) is a treatable form of chronic pancreatitis that has been increasingly recognised over the last decade. We set out to better understand the current burden of AIP at ...several academic institutions diagnosed using the International Consensus Diagnostic Criteria, and to describe long-term outcomes, including organs involved, treatments, relapse frequency and long-term sequelae.
23 institutions from 10 different countries participated in this multinational analysis. A total of 1064 patients meeting the International Consensus Diagnostic Criteria for type 1 (n=978) or type 2 (n=86) AIP were included. Data regarding treatments, relapses and sequelae were obtained.
The majority of patients with type 1 (99%) and type 2 (92%) AIP who were treated with steroids went into clinical remission. Most patients with jaundice required biliary stent placement (71% of type 1 and 77% of type 2 AIP). Relapses were more common in patients with type 1 (31%) versus type 2 AIP (9%, p<0.001), especially those with IgG4-related sclerosing cholangitis (56% vs 26%, p<0.001). Relapses typically occurred in the pancreas or biliary tree. Retreatment with steroids remained effective at inducing remission with or without alternative treatment, such as azathioprine. Pancreatic duct stones and cancer were uncommon sequelae in type 1 AIP and did not occur in type 2 AIP during the study period.
AIP is a global disease which uniformly displays a high response to steroid treatment and tendency to relapse in the pancreas and biliary tree. Potential long-term sequelae include pancreatic duct stones and malignancy, however they were uncommon during the study period and require additional follow-up. Additional studies investigating prevention and treatment of disease relapses are needed.
Pathogens possess the ability to adapt and survive in some host species but not in others-an ecological trait known as host tropism. Transmitted through ticks and carried mainly by mammals and birds, ...the Lyme disease (LD) bacterium is a well-suited model to study such tropism. Three main causative agents of LD, Borrelia burgdorferi, B. afzelii, and B. garinii, vary in host ranges through mechanisms eluding characterization. By feeding ticks infected with different Borrelia species, utilizing feeding chambers and live mice and quail, we found species-level differences in bacterial transmission. These differences localize on the tick blood meal, and specifically complement, a defense in vertebrate blood, and a polymorphic bacterial protein, CspA, which inactivates complement by binding to a host complement inhibitor, Factor H (FH). CspA selectively confers bacterial transmission to vertebrates that produce FH capable of allele-specific recognition. CspA is the only member of the Pfam54 gene family to exhibit host-specific FH-binding. Phylogenetic analyses revealed convergent evolution as the driver of such uniqueness, and that FH-binding likely emerged during the last glacial maximum. Our results identify a determinant of host tropism in Lyme disease infection, thus defining an evolutionary mechanism that shapes host-pathogen associations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The intrinsic foot muscles maintain the medial longitudinal arch and aid in force distribution and postural control during gait. Impaired intrinsic foot-muscle function has been linked to various ...foot conditions. Several rehabilitative exercises have been proposed to improve it; however, literature that identifies which individual muscles are activated during specific intrinsic foot-muscle exercises is lacking.
To describe changes in activation of the intrinsic plantar foot muscles after 4 exercises as measured with T2 magnetic resonance imaging (MRI).
Descriptive laboratory study.
Research laboratory.
Eight healthy National Collegiate Athletic Association Division I collegiate cross-country and track athletes (5 men and 3 women: age = 20 ± 0.93 years, height = 180.98 ± 10.84 cm, mass = 70.91 ± 7.82 kg).
Participants underwent T2 MRI before and after each exercise. They completed 1 set of 40 repetitions of each exercise (short-foot exercise, toes spread out, first-toe extension, second- to fifth-toes extension).
Percentage increases in muscle activation of the abductor hallucis, flexor digitorum brevis, abductor digiti minimi, quadratus plantae, flexor digiti minimi, adductor hallucis oblique, flexor hallucis brevis, and interossei and lumbricals (analyzed together) after each exercise were assessed using T2 MRI.
All muscles showed increased activation after all exercises. The mean percentage increase in activation ranged from 16.7% to 34.9% for the short-foot exercise, 17.3% to 35.2% for toes spread out, 13.1% to 18.1% for first-toe extension, and 8.9% to 22.5% for second- to fifth-toes extension. All increases in activation had associated 95% confidence intervals that did not cross zero.
Each of the 4 exercises was associated with increased activation in all of the plantar intrinsic foot muscles evaluated. These results may have clinical implications for the prescription of specific exercises to target individual intrinsic foot muscles.
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