It's all about timing.

In the formation of long-term memories, a "spaced" distribution of study sessions is more beneficial than closely spaced "massed" study sessions. Pagani et al. (2009) examine the molecular basis of this spacing effect in Drosophila and find a role for the SHP2 homolog, corkscrew, an activator of Ras/MAPK signaling, in establishing optimal spacing intervals.

Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD.

BACKGROUND: Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking. METHODS: In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 µg or 160 µg of budesonide], a LAMA [18 µg of glycopyrrolate], and a LABA [9.6 µg of formoterol]) or one of two dual therapies (18 µg of glycopyrrolate plus 9.6 µg of formoterol or 320 µg of budesonide plus 9.6 µg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only. RESULTS: The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-µg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-µg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-µg-budesonide triple therapy than with glycopyrrolate-formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-µg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group. CONCLUSIONS: Triple therapy with twice-daily budesonide (at either the 160-µg or 320-µg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.).

Extremal Kerr Black Holes as Amplifiers of New Physics.

We show that extremal Kerr black holes are sensitive probes of new physics. Stringy or quantum corrections to general relativity are expected to generate higher-curvature terms in the gravitational action. We show that in the presence of these terms, asymptotically flat extremal rotating black holes have curvature singularities on their horizon. Furthermore, near-extremal black holes can have large yet finite tidal forces for infalling observers. In addition, we consider five-dimensional extremal charged black holes and show that higher-curvature terms can have a large effect on the horizon geometry.

Aspects of molar form and dietary proclivities of African colobines.

This study investigates aspects of molar form in three African colobine species: Colobus polykomos, Colobus angolensis, and Piliocolobus badius. Our samples of C. polykomos and P. badius are from the Taï Forest, Ivory Coast; our sample of C. angolensis is from Diani, Kenya. To the extent that protective layers surrounding seeds are hard, we predicted that molar features related to hard-object feeding would be more pronounced in Colobus than they are Piliocolobus, as seed-eating generally occurs at higher frequencies in species of the former. We further predicted that among the colobines we studied, these features would be most pronounced in Taï Forest C. polykomos, which feeds on Pentaclethra macrophylla seeds encased within hard and tough seed pods. We compared overall enamel thickness, enamel thickness distribution, absolute crown strength, cusp tip geometry, and flare among molar samples. Sample sizes per species and molar type varied per comparison. We predicted differences in all variables except overall enamel thickness, which we expected would be invariant among colobines as a result of selection for thin enamel in these folivorous species. Of the variables we examined, only molar flare differed significantly between Colobus and Piliocolobus. Our findings suggest that molar flare, an ancient feature of cercopithecoid molars, was retained in Colobus but not in Piliocolobus, perhaps as a result of differences in the seed-eating proclivities of the two genera. Contrary to predictions, none of the aspects of molar form we investigated tracked current dietary differences in seed-eating between the two Colobus species. Finally, we explored the possibility that molar flare and absolute crown strength, when analyzed together, might afford greater differentiation among these colobine species. A multivariate t test of molar flare and absolute crown strength differentiated C. polykomos and P. badius, possibly reflecting known niche divergence between these two sympatric Taï Forest species.

Alzheimer's Disease: A Brief History of Immunotherapies Targeting Amyloid ß.

Alzheimer's disease (AD) is the most common form of dementia and may contribute to 60-70% of cases. Worldwide, around 50 million people suffer from dementia and the prediction is that the number will more than triple by 2050, as the population ages. Extracellular protein aggregation and plaque deposition as well as accumulation of intracellular neurofibrillary tangles, all leading to neurodegeneration, are the hallmarks of brains with Alzheimer's disease. Therapeutic strategies including active and passive immunizations have been widely explored in the last two decades. Several compounds have shown promising results in many AD animal models. To date, only symptomatic treatments are available and because of the alarming epidemiological data, novel therapeutic strategies to prevent, mitigate, or delay the onset of AD are required. In this mini-review, we focus on our understanding of AD pathobiology and discuss current active and passive immunomodulating therapies targeting amyloid-ß protein.

A scalable and highly immunogenic virus-like particle-based vaccine against SARS-CoV-2.

BACKGROUND: SARS-CoV-2 caused one of the most devastating pandemics in the recent history of mankind. Due to various countermeasures, including lock-downs, wearing masks, and increased hygiene, the virus has been controlled in some parts of the world. More recently, the availability of vaccines, based on RNA or adenoviruses, has greatly added to our ability to keep the virus at bay; again, however, in some parts of the world only. While available vaccines are effective, it would be desirable to also have more classical vaccines at hand for the future. Key feature of vaccines for long-term control of SARS-CoV-2 would be inexpensive production at large scale, ability to make multiple booster injections, and long-term stability at 4℃. METHODS: Here, we describe such a vaccine candidate, consisting of the SARS-CoV-2 receptor-binding motif (RBM) grafted genetically onto the surface of the immunologically optimized cucumber mosaic virus, called CuMVTT -RBM. RESULTS: Using bacterial fermentation and continuous flow centrifugation for purification, the yield of the production process is estimated to be >2.5 million doses per 1000-litre fermenter run. We demonstrate that the candidate vaccine is highly immunogenic in mice and rabbits and induces more high avidity antibodies compared to convalescent human sera. The induced antibodies are more cross-reactive to mutant RBDs of variants of concern (VoC). Furthermore, antibody responses are neutralizing and long-lived. In addition, the vaccine candidate was stable for at least 14 months at 4℃. CONCLUSION: Thus, the here presented VLP-based vaccine may be a good candidate for use as conventional vaccine in the long term.

Comparative description and taxonomic affinity of 3.7-million-year-old hominin mandibles from Woranso-Mille (Ethiopia).

Fossil discoveries of early Australopithecus species from Woranso-Mille have played a significant role in improving our understanding of mid-Pliocene hominin evolution and diversity. Here, we describe two mandibles with dentitions, recovered from sediments immediately above a tuff radiometrically dated to 3.76 ± 0.02 Ma, and assess their taxonomic affinity. The two mandibles (MSD-VP-5/16 and MSD-VP-5/50) show morphological similarities with both Australopithecus anamensis and Australopithecus afarensis. Some of the unique features that distinguish Au. anamensis from Au. afarensis are present in the mandibles, which also share a few derived features with Au. afarensis. Their retention of more Kanapoi Au. anamensis-like traits, compared to the fewer derived features they share with Au. afarensis, and the presence of Au. anamensis at Woranso-Mille in 3.8-million-year-old deposits, lends support to their assignment to Au. anamensis. However, it is equally arguable that the few derived dentognathic features they share with Au. afarensis could be taxonomically more significant, making it difficult to conclusively assign these specimens to either species. Regardless of which species they are assigned to, the mosaic nature of the dentognathic morphology and geological age of the two mandibles lends further support to the hypothesized ancestor-descendant relationship between Au. anamensis and Au. afarensis. However, there is now limited fossil evidence indicating that these two species may have overlapped in time. Hence, the last appearance of Au. anamensis and first appearance of Au. afarensis are currently unknown. Recovery of Australopithecus fossils from 4.1 to 3.8 Ma is critical to further address the timing of these events.

A simple rule governs the evolution and development of hominin tooth size.

The variation in molar tooth size in humans and our closest relatives (hominins) has strongly influenced our view of human evolution. The reduction in overall size and disproportionate decrease in third molar size have been noted for over a century, and have been attributed to reduced selection for large dentitions owing to changes in diet or the acquisition of cooking. The systematic pattern of size variation along the tooth row has been described as a 'morphogenetic gradient' in mammal, and more specifically hominin, teeth since Butler and Dahlberg. However, the underlying controls of tooth size have not been well understood, with hypotheses ranging from morphogenetic fields to the clone theory. In this study we address the following question: are there rules that govern how hominin tooth size evolves? Here we propose that the inhibitory cascade, an activator-inhibitor mechanism that affects relative tooth size in mammals, produces the default pattern of tooth sizes for all lower primary postcanine teeth (deciduous premolars and permanent molars) in hominins. This configuration is also equivalent to a morphogenetic gradient, finally pointing to a mechanism that can generate this gradient. The pattern of tooth size remains constant with absolute size in australopiths (including Ardipithecus, Australopithecus and Paranthropus). However, in species of Homo, including modern humans, there is a tight link between tooth proportions and absolute size such that a single developmental parameter can explain both the relative and absolute sizes of primary postcanine teeth. On the basis of the relationship of inhibitory cascade patterning with size, we can use the size at one tooth position to predict the sizes of the remaining four primary postcanine teeth in the row for hominins. Our study provides a development-based expectation to examine the evolution of the unique proportions of human teeth.

Reduced All-Cause Mortality in the ETHOS Trial of Budesonide/Glycopyrrolate/Formoterol for Chronic Obstructive Pulmonary Disease. A Randomized, Double-Blind, Multicenter, Parallel-Group Study.

Rationale: In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 of 8,509 patients were missing vital status at Week 52 in the original analyses.Objectives: To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses.Methods: Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 µg of BGF (BGF 320), 160/18/9.6 µg of BGF (BGF 160), 18/9.6 µg of GFF, or 320/9.6 µg of budesonide/formoterol fumarate (BFF) (all delivered via a single metered-dose Aerosphere inhaler). Time to death (all-cause) was a prespecified secondary endpoint.Measurements and Main Results: In the final retrieved dataset, which included Week 52 vital status for 99.6% of the intent-to-treat population, risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; 95% confidence interval, 0.33-0.80; unadjusted P = 0.0035). There were no significant differences in mortality when comparing BGF 320 with BFF (hazard ratio, 0.72; 95% confidence interval, 0.44-1.16; P = 0.1721), nor were significant differences observed when comparing BGF 160 against either dual comparator. Results were similar when the first 30, 60, or 90 days of treatment were excluded from the analysis. Deaths from cardiovascular causes occurred in 0.5%, 0.8%, 1.4%, and 0.5% of patients in the BGF 320, BGF 160, GFF, and BFF groups, respectively.Conclusions: Using final retrieved vital status data, triple therapy with BGF 320 reduced the risk of death compared with GFF, but was not shown to significantly reduce the risk of death compared with BFF, in patients with COPD. Triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) was not shown to significantly reduce the risk of death compared with the dual therapy comparators.

Listeria monocytogenes is a solvent tolerant organism secreting a solvent stable lipase: potential biotechnological applications.

PURPOSE: The emerging biobased economy will require robust, adaptable, organisms for the production and processing of biomaterials as well as for bioremediation. Recently, the search for solvent tolerant organisms and solvent tolerant enzymes has intensified. Resilient organisms secreting solvent stable lipases are of particular interest for biotechnological applications. METHODS: Screening of soil samples for lipase-producing organisms was carried out on Rhodamine B plates. The most productive lipase-producing organisms were further screened for their resistance to solvents commonly used in biotechnological applications. RESULTS: In the course of screening, one of the isolated organisms that exhibited extracellular lipase activity, was identified as the human pathogen Listeria monocytogenes through 16S rRNA sequencing. Further exploration revealed that this organism was resistant to solvents ranging from log P - 0.81 to 4.0. Moreover, in the presence of these solvents, L. monocytogenes secreted an extracellular, solvent tolerant, lipase activity. This lipase retained approximately 80% activity when incubated in 30% (v/v) methanol for 24 h. CONCLUSION: These findings identify L. monocytogenes as a potentially useful organism for biotechnological applications. However, the fact that Listeria is a pathogen is problematic and it will require the use of non-pathogenic or attenuated Listeria strains for practical applications. Nonetheless, the ability to adapt to rapidly changing environmental conditions, to grow at low temperatures, to resist solvents and to secrete an extracellular solvent tolerant lipase are unique and highly useful characteristics. The potential application of L. monocytogenes in wastewater bioremediation and plastics degradation is discussed.

Verticalization for Refractory Intracranial Hypertension: A Case Series.

BACKGROUND: Severe intracranial hypertension is strongly associated with mortality. Guidelines recommend medical management involving sedation, hyperosmotic agents, barbiturates, hypothermia, and surgical intervention. When these interventions are maximized or are contraindicated, refractory intracranial hypertension poses risk for herniation and death. We describe a novel intervention of verticalization for treating intracranial hypertension refractory to aggressive medical treatment. METHODS: This study was a single-center retrospective review of six cases of refractory intracranial hypertension in a tertiary care center. All patients were treated with a standard-of-care algorithm for lowering intracranial pressure (ICP) yet maintained an ICP greater than 20 mmHg. They were then treated with verticalization for at least 24 h. We compared the median ICP, the number of ICP spikes greater than 20 mmHg, and the percentage of ICP values greater than 20 mmHg in the 24 h before verticalization vs. after verticalization. We assessed the use of hyperosmotic therapies and any changes in the mean arterial pressure and cerebral perfusion pressure related with the intervention. RESULTS: Five patients were admitted with subarachnoid hemorrhage and one with intracerebral hemorrhage. All patients had ICP monitoring by external ventricular drain. The median opening pressure was 30 mmHg (25th-75th interquartile range 22.5-30 mmHg). All patients demonstrated a reduction in ICP after verticalization, with a significant decrease in the median ICP (12 vs. 8 mmHg; p < 0.001), the number of ICP spikes (12 vs. 2; p < 0.01), and the percentage of ICP values greater than 20 mmHg (50% vs. 8.3%; p < 0.01). There was a decrease in total medical interventions after verticalization (79 vs. 41; p = 0.05) and a lower total therapy intensity level score after verticalization. The most common adverse effects included asymptomatic bradycardia (n = 3) and pressure wounds (n = 4). CONCLUSIONS: Verticalization is an effective noninvasive intervention for lowering ICP in intracranial hypertension that is refractory to aggressive standard management and warrants further study.

Direct measurement of CTDIw on helical CT scans.

PURPOSE: Medical physics computed tomography (CT) practice involves measurements to determine CTDIvol on representative clinical CT protocols. In current practice the majority of CT exams employ helical scans. To determine CTDIvol for a helical scan, one measures CTDIw with an axial scan, then divides by the pitch. Problems arise in CT units where one is unable to select an axial scan with the same detector configuration and pre-patient (bowtie) filtration that is employed on the helical scan. Presented is a method to measure CTDIw on helical scans. METHODS: The body and head CTDI phantoms were supported on the gantry shroud with brackets attached to the phantom. The phantom is above the tabletop and remains stationary during helical scans as the table moves beneath the phantom. With the phantom stationary, the CTDIw associated with head and body helical scans was measured. CTDIw was also measured for head and body axial scans with the same pre-patient filtrations and detector configurations. RESULTS: For both the head and body CTDI phantom the agreement between the axial and helical CTDIw measurements was <1.5%. CONCLUSIONS: Body and head CTDIw and CTDIvol can be directly measured by employing helical scans with the method in this paper.

Benralizumab for adolescent patients with severe, eosinophilic asthma: Safety and efficacy after 3 years of treatment.

BACKGROUND: Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of benralizumab in the first year of BORA (year 2 of treatment) have been reported. OBJECTIVE: We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA. METHODS: Patients on benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) in SIROCCO/CALIMA continued their regimens in BORA (Q4W/Q4W and Q8W/Q8W, respectively), whereas placebo patients were rerandomized 1:1 to benralizumab (placebo/Q4W and placebo/Q8W, respectively) for 108 weeks. The primary outcome was safety; secondary outcomes included reduction in annual asthma exacerbation rate and change from baseline in prebronchodilator FEV1. RESULTS: Adolescents (N = 86) were treated with benralizumab Q8W (n = 61) or Q4W (n = 25); 69 completed treatment (Q8W: n = 51; Q4W: n = 18). For Q4W and Q8W regimens, rates of treatment-emergent adverse events were 68% (17 of 25) and 74% (45 of 61), respectively, rates of treatment-emergent adverse events (TEAEs) were 68% (17/25) and 74% (45/61), TEAEs leading to discontinuation were 4% (1/25) and 0%, serious AEs were 8% (2/25) and 7% (4/61), and no deaths occurred. In efficacy analyses, 69% (42 of 61) Q8W patients were exacerbation-free (placebo/Q8W: 62% [18 of 29], Q8W/Q8W: 75% [24 of 32]). Mean ± SD change in FEV1 at week 108 versus BORA baseline was 0.327 ± 0.452 L (placebo/Q8W) and 0.323 ± 0.558 L (Q8W/Q8W). CONCLUSIONS: Safety and efficacy profiles in this 2-year extension study (up to 3 years of benralizumab treatment in adolescents) were consistent with previous findings.

The Landscape of Perception: Racial Differences in How Disability Is Viewed Among Older-Adult Cancer Survivors.

This paper compares disability perceptions of Black with white older cancer survivors' to document racial disparities in these perceptions and the factors that contribute to them. The data are from a randomly selected tumor registry sample of 321 older adult cancer survivors from an NCI funded study. OLS regression models of disability perceptions, nested by race, examined the effects cancer and non-cancer health factors along with important covariates. Black older adult cancer survivors perceived themselves to be more disabled than did white survivors. Multivariate analyses showed a strong relationship between functional difficulties and disability perceptions for both Black and white survivors. However cancer-related factors such as continuing symptoms of the illness or treatment were relatively more important for Blacks. The findings suggest that race and cancer are both important factors in our understanding of disability in later life. These findings can then inform clinical best practices among minority older adults.

Extracellular secretion of a cutinase with polyester-degrading potential by E. coli using a novel signal peptide from Amycolatopsis mediterranei.

Recent studies in this laboratory showed that an extracellular cutinase from A. mediterranei (AmCut) was able to degrade the plastics polycaprolactone and polybutylene succinate. Such plastics can be slow to degrade in soils due to a lack of efficient polyester degrading organisms. AmCut also showed potential for the biocatalytic synthesis of esters by reverse hydrolysis. The gene for AmCut has an upstream leader sequence whose transcript is not present in the purified enzyme. In this study, we show using predictive modelling, that this sequence codes for an N-terminal signal peptide that directs transmembrane expression via the Sec secretion pathway. E. coli is a useful host for recombinant enzymes used in biocatalysis due to the ease of genetic manipulation in this organism, which allows tuning of enzymes for specific applications, by mutagenesis. When a truncated GST-tagged AmCut gene (lacking its signal peptide) was expressed in E. coli, all cutinase activity was observed in the cytosolic fraction. However, when GST-tagged AmCut was expressed in E. coli along with its native signal peptide, cutinase activity was observed in both the periplasmic space and the culture medium. This finding revealed that the native signal peptide of a Gram-positive organism (AmCut) was being recognised by the Gram-negative (E. coli) Sec transmembrane transport system. AmCut was transported into E. coli's periplasmic space from where it was released into the culture medium. Surprisingly, the presence of a bulky GST tag at the N-terminus of the signal peptide did not hinder transmembrane targeting. Although the periplasmic targeting was unexpected, it is not unprecedented due to the conservation of the Sec pathway across species. It was more surprising that AmCut was secreted from the periplasmic space into the culture medium. This suggests that extracellular AmCut translocation across the E. coli outer membrane may involve non-classical secretion pathways. This tuneable recombinant E. coli expressing extracellular AmCut may be useful for degradation of polyester substrates in the environment; this and other applications are discussed.

Admission Features Associated With Paroxysmal Sympathetic Hyperactivity After Traumatic Brain Injury: A Case-Control Study.

OBJECTIVES: Paroxysmal sympathetic hyperactivity occurs in a subset of critically ill traumatic brain injury patients and has been associated with worse outcomes after traumatic brain injury. The goal of this study was to identify admission risk factors for the development of paroxysmal sympathetic hyperactivity in traumatic brain injury patients. DESIGN: Retrospective case-control study of age- and Glasgow Coma Scale-matched traumatic brain injury patients. SETTING: Neurotrauma ICU at the R. Adams Cowley Shock Trauma Center of the University of Maryland Medical System, January 2016 to July 2018. PATIENTS: Critically ill adult traumatic brain injury patients who underwent inpatient monitoring for at least 14 days were included. Cases were identified based on treatment for paroxysmal sympathetic hyperactivity with institutional first-line therapies and were confirmed by retrospective tabulation of established paroxysmal sympathetic hyperactivity diagnostic and severity criteria. Cases were matched 1:1 by age and Glasgow Coma Scale to nonparoxysmal sympathetic hyperactivity traumatic brain injury controls, yielding 77 patients in each group. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Admission characteristics independently predictive of paroxysmal sympathetic hyperactivity included male sex, higher admission systolic blood pressure, and initial CT evidence of diffuse axonal injury, intraventricular hemorrhage/subarachnoid hemorrhage, complete cisternal effacement, and absence of contusion. Paroxysmal sympathetic hyperactivity cases demonstrated significantly worse neurologic outcomes upon hospital discharge despite being matched for injury severity at admission. CONCLUSIONS: Several anatomical, epidemiologic, and physiologic risk factors for clinically relevant paroxysmal sympathetic hyperactivity can be identified on ICU admission. These features help characterize paroxysmal sympathetic hyperactivity as a clinical-pathophysiologic phenotype associated with worse outcomes after traumatic brain injury.

Boundary Causality Violating Metrics in Holography.

Even for holographic theories that obey boundary causality, the full bulk Lorentzian path integral includes metrics that violate this condition. This leads to the following puzzle: the commutator of two field theory operators at space-like-separated points on the boundary must vanish. However, if these points are causally related in a bulk metric, then the bulk calculation of the commutator will be nonzero. It would appear that the integral over all metrics of this commutator must vanish exactly for holography to hold. This is puzzling since it must also be true if the commutator is multiplied by any other operator. Upon a careful treatment of boundary conditions in holography, we show how the bulk path integral leads to a natural resolution of this puzzle.

Two-year integrated steroid-sparing analysis and safety of benralizumab for severe asthma.

OBJECTIVE: Treatment with benralizumab significantly reduces exacerbations and improves lung function after 1 year and decreases oral corticosteroid (OCS) use after 28 weeks for patients with severe, uncontrolled eosinophilic asthma. We assessed whether these effects on OCS reduction are sustained for up to an additional year of treatment while maintaining an acceptable safety profile. METHODS: Data on OCS maintenance dosage were collected for adult patients with baseline blood eosinophil counts ≥150 cells/µL treated with add-on benralizumab 30 mg (every 4 [Q4W] or 8 weeks [Q8W; first three doses Q4W]) from the 28-week ZONDA study and were integrated with results from the predefined 56-week adult completion phase of the BORA extension study. Efficacy and safety were summarized descriptively. RESULTS: For patients receiving benralizumab Q8W, the median daily OCS dosage reduction of 75% from baseline to end of treatment achieved in ZONDA was sustained at the end of the BORA extension period (median 67% reduction from baseline). This was estimated to result in a median cumulative OCS dosage of 2.98 g over the 1.5-year period for patients receiving benralizumab Q8W compared with 5.74 g if these patients had remained on their baseline OCS dosages prior to benralizumab initiation. All adverse event rates were similar between the BORA extension and ZONDA periods, with no new or unexpected safety findings. CONCLUSION: This benralizumab 1.5-year integrated analysis demonstrates that OCS reductions and safety were maintained with further follow up and supports long-term use of benralizumab for patients with severe, uncontrolled eosinophilic asthma.

Assessing the Accuracy of a Deep Learning Method to Risk Stratify Indeterminate Pulmonary Nodules.

Rationale: The management of indeterminate pulmonary nodules (IPNs) remains challenging, resulting in invasive procedures and delays in diagnosis and treatment. Strategies to decrease the rate of unnecessary invasive procedures and optimize surveillance regimens are needed.Objectives: To develop and validate a deep learning method to improve the management of IPNs.Methods: A Lung Cancer Prediction Convolutional Neural Network model was trained using computed tomography images of IPNs from the National Lung Screening Trial, internally validated, and externally tested on cohorts from two academic institutions.Measurements and Main Results: The areas under the receiver operating characteristic curve in the external validation cohorts were 83.5% (95% confidence interval [CI], 75.4-90.7%) and 91.9% (95% CI, 88.7-94.7%), compared with 78.1% (95% CI, 68.7-86.4%) and 81.9 (95% CI, 76.1-87.1%), respectively, for a commonly used clinical risk model for incidental nodules. Using 5% and 65% malignancy thresholds defining low- and high-risk categories, the overall net reclassifications in the validation cohorts for cancers and benign nodules compared with the Mayo model were 0.34 (Vanderbilt) and 0.30 (Oxford) as a rule-in test, and 0.33 (Vanderbilt) and 0.58 (Oxford) as a rule-out test. Compared with traditional risk prediction models, the Lung Cancer Prediction Convolutional Neural Network was associated with improved accuracy in predicting the likelihood of disease at each threshold of management and in our external validation cohorts.Conclusions: This study demonstrates that this deep learning algorithm can correctly reclassify IPNs into low- or high-risk categories in more than a third of cancers and benign nodules when compared with conventional risk models, potentially reducing the number of unnecessary invasive procedures and delays in diagnosis.

Novel Facet of an Old Dietary Molecule? Direct Influence of Caffeine on Glucose and Biogenic Amine Handling by Human Adipocytes.

Caffeine is a plant alkaloid present in food and beverages consumed worldwide. It has high lipid solubility with recognized actions in the central nervous system and in peripheral tissues, notably the adipose depots. However, the literature is scant regarding caffeine's influence on adipocyte functions other than lipolysis, such as glucose incorporation into lipids (lipogenesis) and amine oxidation. The objective of this study was to explore the direct effects of caffeine and of isobutylmethylxanthine (IBMX) on these adipocyte functions. Glucose transport into fat cells freshly isolated from mice, rats, or humans was monitored by determining [3H]-2-deoxyglucose (2-DG) uptake, while the incorporation of radiolabeled glucose into cell lipids was used as an index of lipogenic activity. Oxidation of benzylamine by primary amine oxidase (PrAO) was inhibited by increasing doses of caffeine in human adipose tissue preparations with an inhibition constant (Ki) in the millimolar range. Caffeine inhibited basal and insulin-stimulated glucose transport as well as lipogenesis in rodent adipose cells. The antilipogenic action of caffeine was also observed in adipocytes from mice genetically invalidated for PrAO activity, indicating that PrAO activity was not required for lipogenesis inhibition. These caffeine inhibitory properties were extended to human adipocytes: relative to basal 2-DG uptake, set at 1.0 ± 0.2 for 6 individuals, 0.1 mM caffeine tended to reduce uptake to 0.83 ± 0.08. Insulin increased uptake by 3.86 ± 1.11 fold when tested alone at 100 nM, and by 3.21 ± 0.80 when combined with caffeine. Our results reinforce the recommendation of caffeine's potential in the treatment or prevention of obesity complications.