Search

We evaluated the effects of a discrimination training procedure for establishing praise as a reinforcer for three children with autism spectrum disorder. After establishing two praise words as discriminative stimuli and two nonsense words as S-deltas, we evaluated whether the stimuli then functioned as reinforcers by presenting each stimulus as a consequence for a new response. The results demonstrated that previously neutral praise words functioned as reinforcers and nonsense words did not. As in previous studies on establishing reinforcers, the effects were transitory, and praise words did not continue to function as reinforcers after repeated exposure without discrimination training. Recommendations are provided for future research and maintaining reinforcement effects.

In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41-0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19-38%) and 9% (90% CI = 2-25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 .

Abstract A novel model called PyIRI was recently developed. It constructs the ionospheric electron density for the entire day and on the entire global grid in one computation, which has a very low computational overhead. PyIRI introduced a novel approach to the computation of the global and diurnal functions and their matrix multiplication with Consultative Committee on International Radio (CCIR) coefficients or the International Union of Radio Science (URSI) coefficients, that enabled this global approach for the density specification. Since the International Reference Ionosphere‐based Real‐Time Assimilative Model (IRTAM) produces coefficients in a similar format as CCIR/URSI coefficients, the PyIRI computational approach was extended to work with IRTAM coefficients. This technical note describes the PyIRTAM software and provides usage examples. The PyIRTAM tool is made publicly available through PyPI and GitHub.

The adoption, of human excreta compost improves soil health and yields of crops. It also supports baobab cultivation, livelihoods, nutrition, and incomes, in a healthy sanitary safe environment. This study examines the farmers’ adoption perception of human excreta compost from the Urine Diversion Dry Toilets (UDDT). It links the compost to the cultivation of early maturing baobab seedlings. It used a random sampling to select 139 respondents from 230 households in 6 communities of Adaklu. We test for the differences between the characteristics of the participants interested in adopting and those with no interest to adopt the two technologies. The study also used a probit model to investigate the influence of the characteristics of the households on the adoption perception of two technologies. The results show that significant differences exist in the ages, cereal, roots, and tuber cultivation as well as the perception of features of baobab seedlings, between the individuals willing to adopt the compost or not. Contrarily, significant differences exist between the age, sex, farm size, cereals, root, and tuber cultivation, as well as the features of the new baobab seedlings between adopters and non-adopters. The probit model results show that years of farming experience, farm size, multiple uses of the baobab and its early fruiting nature exert positive effects on the adoption of the two technologies. Contrarily, the younger people are more likely to accept the technologies more than older ones. Also, formal education is also likely to lead to low adoption of the technologies. Besides, as the male respondents are more likely to adopt the baobab cultivation than the females, larger households could also adopt the compost than the smaller ones. The paper concludes that these factors influence the adoption perception of the respondents and, therefore, recommends that these factors should be considered in promoting the compost and the early maturing baobab seedling adoption.

Milk oligosaccharides (MOs) can be prebiotic and antiadhesive, while fatty acids (MFAs) can be antimicrobial. Both have been associated with milk microbes or mammary gland inflammation in humans. Relationships between these milk components and milk microbes or inflammation have not been determined for cows and could help elucidate a novel approach for the dairy industry to promote desired milk microbial composition for improvement of milk quality and reduction of milk waste. We aimed to determine relationships among milk microbiota, MFAs, MOs, lactose, and somatic cell counts (SCC) from Holstein cows, using our previously published data. Raw milk samples were collected at three time points, ranging from early to late lactation. Data were analyzed using linear mixed-effects modeling and repeated-measures correlation. Unsaturated MFA and short-chain MFA had mostly negative relationships with potentially pathogenic genera, including Corynebacterium, Pseudomonas, and an unknown Enterobacteriaceae genus but numerous positive relationships with symbionts Bifidobacterium and Bacteroides. Conversely, many MOs were positively correlated with potentially pathogenic genera (e.g., Corynebacterium, Enterococcus, and Pseudomonas), and numerous MOs were negatively correlated with the symbiont Bifidobacterium. The neutral, nonfucosylated MO composed of eight hexoses had a positive relationship with SCC, while lactose had a negative relationship with SCC. One interpretation of these trends might be that in milk, MFAs disrupt primarily pathogenic bacterial cells, causing a relative increase in abundance of beneficial microbial taxa, while MOs respond to and act on pathogenic taxa primarily through antiadhesive methods. Further research is needed to confirm the potential mechanisms driving these correlations. IMPORTANCE Bovine milk can harbor microbes that cause mastitis, milk spoilage, and foodborne illness. Fatty acids found in milk can be antimicrobial and milk oligosaccharides can have antiadhesive, prebiotic, and immune-modulatory effects. Relationships among milk microbes, fatty acids, oligosaccharides, and inflammation have been reported for humans. To our knowledge, associations among the milk microbial composition, fatty acids, oligosaccharides, and lactose have not been reported for healthy lactating cows. Identifying these potential relationships in bovine milk will inform future efforts to characterize direct and indirect interactions of the milk components with the milk microbiota. Since many milk components are associated with herd management practices, determining if these milk components impact milk microbes may provide valuable information for dairy cow management and breeding practices aimed at minimizing harmful and spoilage-causing microbes in raw milk.

BackgroundWhether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown.MethodsIn a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated.ResultsAt a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group.ConclusionsAmong patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

Studies employing multiple-schedule arrangements to bring social approaches (e.g., requesting attention, raising hand) under stimulus control have commonly used correlated contrived, continuous stimuli with at least one condition (e.g., displaying a green stimulus when attention is available and a red stimulus when it is not). Although imposing these correlates may have advantages for teaching, it may be impractical or stigmatizing to use them indefinitely in a learner's natural environment. The purpose of the current study was to extend previous research by using rules as naturalistic schedule correlates in a multiple-schedule arrangement. We evaluated the effects of multiple schedules with spoken rules (naturalistic, noncontinuous correlates) and a written rule (contrived, continuous correlate) on social approaches in three classrooms with adolescents with a variety of special education classifications. Social approaches decreased quickly during independent work periods and remained below criterion for all participants, with a novel teacher, when the written rule was removed, and during maintenance probes. Social validity assessments with the participants and special education teachers indicated high acceptability.

Summary: Why aggressive traits evolve in some species but not in others is poorly understood. We modeled the population dynamics of the extinct Mauritius dodo and Rodrigues solitaire to examine divergent pathways in the evolution of aggression. Whereas the dodo conformed to island syndrome predictions of tameness, its sister-taxon the solitaire evolved strong sexual dimorphism and aggressive traits. We computed rates of change in island size from sea level modeling and connected island size change to population dynamics by integrating a Hawk-Dove game theory model for territory competition with a population model. We find that the rapid rate of decrease in island size likely was an important trigger for the onset of aggressive behavior and that aggressive behavior becomes fixed if a tipping point is reached where island size falls below a critical threshold.

Abstract Prey must balance resource acquisition with predator avoidance for survival and reproduction. To reduce risk of predation, prey may avoid areas with high predator use, but if they are unable to due to resource acquisition requirements, they may instead change their habitat use or movement speed to mitigate predation risk. Prey risk response may depend on spatially or temporally varying forage availability as well as seasonal variation in prey vulnerability and availability of alternate foods for predators. To quantify how prey respond to spatial and temporal variation in risk of brown bear predation, we examined Roosevelt elk (Cervus canadensis roosevelti) spatiotemporal behavior responses to brown bear (Ursus arctos) habitat use on Afognak and Raspberry islands, Alaska, using Global Positioning System location data during elk parturition (20 May–15 June), summer (16 June–20 September), and autumn (21 September–10 November). During parturition and summer, elk used forest and shrub landcover in areas of higher brown bear probability of use. During parturition, elk used areas with lower forage productivity in areas of higher bear probability of use, and movement speed decreased with higher bear probability of use, especially in shrub landcover. During summer, elk used areas with higher forage productivity in areas of higher brown bear probability of use. During autumn, elk were less likely to use areas with higher bear habitat probability of use across landcover categories and forage productivity. During summer and autumn, elk movement speed increased with higher brown bear probability of use. Elk behavioral response to risk of brown bear predation could increase energy expenditure and decrease their ability to acquire forage, therefore negatively impacting survival and reproduction with spatiotemporal variation in risk response potentially amplifying these impacts.

BackgroundTreatment with immune checkpoint inhibitors (ICIs) has been linked to granulomatous and sarcoid-like lesions (GSLs) affecting different organs. This study sought to evaluate GSL incidence in patients with high-risk melanoma treated with cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death 1 (PD1) blockade adjuvant therapy in two clinical trials: ECOG-ACRIN E1609 and SWOG S1404. Descriptions and GSL severity ratings were recorded.MethodsData were collected from ECOG-ACRIN E1609 and SWOG S1404. Descriptive statistics along with GSL severity grades were reported. Additionally, a literature review for such cases was summarized.ResultsA total of 11 GSL cases were reported among 2878 patients treated with either ICI or with High-Dose Interferon Alfa-2b (HDI) in ECOG-ACRIN E1609 and SWOG S1404 trials. Cases were numerically more commonly reported with ipi10, followed by pembrolizumab, ipi3, and HDI, respectively. Most of the cases were grade III. Further, organs involved included lung, mediastinal lymph nodes, skin and subcutaneous tissue, and eye. Furthermore, a summary of 62 reports in the literature was described.ConclusionsGSLs following anti-CTLA4 and anti-PD1 antibody therapy in patients with melanoma were reported unusually. Reported cases ranged in grade from I to III and appeared manageable. Careful attention to these events and their reporting will be essential to better guide practice and management guidelines.

Abstract Sigma-2-ligands (S2L) are characterized by high binding affinities to their cognate sigma-2 receptor, overexpressed in rapidly proliferating tumor cells. As such, S2L were developed as imaging probes (ISO1) or as cancer therapeutics, alone (SV119 [C6], SW43 [C10]) and as delivery vehicles for cytotoxic drug cargoes (C6-Erastin, C10-SMAC). However, the exact mechanism of S2L-induced cytotoxicity remains to be fully elucidated. A series of high-affinity S2L were evaluated regarding their cytotoxicity profiles across cancer cell lines. While C6 and C10 displayed distinct cytotoxicities, C0 and ISO1 were essentially non-toxic. Confocal microscopy and lipidomics analysis in cellular and mouse models revealed that C10 induced increases in intralysosomal free cholesterol and in cholesterol esters, suggestive of unaltered intracellular cholesterol trafficking. Cytotoxicity was caused by cholesterol excess, a phenomenon that contrasts the effects of NPC1 inhibition. RNA-sequencing revealed gene clusters involved in cholesterol homeostasis and ER stress response exclusively by cytotoxic S2L. ER stress markers were confirmed by qPCR and their targeted modulation inhibited or enhanced cytotoxicity of C10 in a predicted manner. Moreover, C10 increased sterol regulatory element-binding protein 2 (SREBP2) and low-density lipoprotein receptor (LDLR), both found to be pro-survival factors activated by ER stress. Furthermore, inhibition of downstream processes of the adaptive response to S2L with simvastatin resulted in synergistic treatment outcomes in combination with C10. Of note, the S2L conjugates retained the ER stress response of the parental ligands, indicative of cholesterol homeostasis being involved in the overall cytotoxicity of the drug conjugates. Based on these findings, we conclude that S2L-mediated cell death is due to free cholesterol accumulation that leads to ER stress. Consequently, the cytotoxic profiles of S2L drug conjugates are proposed to be enhanced via concurrent ER stress inducers or simvastatin, strategies that could be instrumental on the path toward tumor eradication.

Modern treat-to-target management of rheumatoid arthritis (RA) involves titration of drug therapy to achieve remission, requiring close monitoring of disease activity through frequent clinical assessments. Accelerometry offers a novel method for continuous remote monitoring of RA activity by capturing fluctuations in mobility, sedentary behaviours, physical activity and sleep patterns over prolonged periods without the expense, inconvenience and environmental impact of extra hospital visits. We aimed to (a) assess the feasibility, usability and acceptability of wearable devices in patients with active RA; (b) investigate the multivariate relationships within the dataset; and (c) explore the robustness of accelerometry outcomes to downsampling to facilitate future prolonged monitoring. Eleven people with active RA newly starting an arthritis drug completed clinical assessments at 4-week intervals for 12 weeks. Participants wore an Axivity AX6 wrist device (sampling frequency 100 Hz) for 7 days after each clinical assessment. Measures of macro gait (volume, pattern and variability), micro gait (pace, rhythm, variability, asymmetry and postural control of walking), sedentary behaviour (standing, sitting and lying) and physical activity (moderate to vigorous physical activity [MVPA], sustained inactive bouts [SIBs]) and sleep outcomes (sleep duration, wake up after sleep onset, number of awakenings) were recorded. Feasibility, usability and acceptability of wearable devices were assessed using Rabinovich’s questionnaire, principal component (PC) analysis was used to investigate the multivariate relationships within the dataset, and Bland–Altman plots (bias and Limits of Agreement) and Intraclass Correlation Coefficient (ICC) were used to test the robustness of outcomes sampled at 100 Hz versus downsampled at 50 Hz and 25 Hz. Wearable devices obtained high feasibility, usability and acceptability scores among participants. Macro gait outcomes and MVPA (first PC) and micro gait outcomes and number of SIBs (second PC) exhibited the strongest loadings, with these first two PCs accounting for 40% of the variance of the dataset. Furthermore, these device metrics were robust to downsampling, showing good to excellent agreements (ICC ≥ 0.75). We identified two main domains of mobility, physical activity and sleep outcomes of people with RA: micro gait outcomes plus MVPA and micro gait outcomes plus number of SIBs. Combined with the high usability and acceptability of wearable devices and the robustness of outcomes to downsampling, our real-world data supports the feasibility of accelerometry for prolonged remote monitoring of RA disease activity.

AimsWe determined the feasibility and diagnostic performance of segmental 18F-flurpiridaz myocardial blood flow (MBF) measurement by positron emission tomography (PET) compared with the standard territory method, and assessed whether flow metrics provide incremental diagnostic value beyond relative perfusion quantitation (PQ).Methods and resultsAll evaluable pharmacological stress patients from the Phase III trial of 18F-flurpiridaz were included (n = 245) and blinded flow metrics obtained. For each coronary territory, the segmental flow metric was defined as the lowest 17-segment stress MBF (SMBF), myocardial flow reserve (MFR), or relative flow reserve (RFR) value. Diagnostic performances of segmental and territory MBF metrics were compared by receiver operating characteristic (ROC) areas under the curve (AUC). A multiple logistic model was used to evaluate whether flow metrics provided incremental diagnostic value beyond PQ alone. The diagnostic performances of segmental flow metrics were higher than their territory counterparts; SMBF AUC = 0.761 vs. 0.737; MFR AUC = 0.699 vs. 0.676; and RFR AUC = 0.716 vs. 0.635, respectively (P < 0.001 for all). Similar results were obtained for per-vessel coronary artery disease (CAD) ≥70% stenosis categorization and per-patient analyses. Combinatorial analyses revealed that only SMBF significantly improved the diagnostic performance of PQ in CAD ≥50% stenoses, with PQ AUC = 0.730, PQ + segmental SMBF AUC = 0.782 (P < 0.01), and PQ + territory SMBF AUC = 0.771 (P < 0.05). No flow metric improved diagnostic performance when combined with PQ in CAD ≥70% stenoses.ConclusionAssessment of segmental MBF metrics with 18F-flurpiridaz is feasible and improves flow-based epicardial CAD detection. When combined with PQ, only SMBF provides additive diagnostic performance in moderate CAD.

Abstract ANCHOR is a novel assimilative model developed at the U.S. Naval Research Laboratory, which was designed for rapid assimilative runs. ANCHOR uses recently developed PyIRI model for the background and for the formation of the background covariance matrix. It only takes a few minutes for ANCHOR to complete the data assimilation (DA) for one day, including data pre‐processing and model set up. ANCHOR extracts ionospheric parameters from radio occultation (RO) and ionosonde data using PyIRI formalism and assimilates them as point measurements into maps of the background parameters using a Kalman Filter approach. This paper introduces the ANCHOR algorithm, discusses its coordinate system and background, explains the background covariance formation, discusses the extraction of the ionospheric parameters from the data and the assimilation process, and, finally, shows the results of the observing system simulation experiment with synthetic data simulated using the SAMI3 model. ANCHOR reduces the root mean square errors in the analysis by more than a half for all of the ionospheric parameters in comparison to the background. Finally, this paper discusses advantages and limitations of the parametrized ionospheric DA, highlighting the avenues for its future improvement.

Background Patients may prefer percutaneous coronary intervention (PCI) over coronary artery bypass graft (CABG) surgery, despite heart team recommendations. The outcomes in such patients have not been examined. We sought to examine the results of PCI in patients who were recommended for but declined CABG. Methods and Results Consecutive patients with stable ischemic heart disease and unprotected left main or 3‐vessel disease or Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery score >22 who underwent PCI after heart team review between 2013 and 2020 were included. Patients were categorized into 3 groups according to heart team recommendations on the basis of appropriate use criteria: (1) PCI‐recommended; (2) CABG‐eligible but refused CABG (CABG‐refusal); and (3) CABG‐ineligible. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. The study included 3687 patients undergoing PCI (PCI‐recommended, n=1718 [46.6%]), CABG‐refusal (n=1595 [43.3%]), and CABG‐ineligible (n=374 [10.1%]). Clinical and procedural risk increased across the 3 groups, with the highest comorbidity burden in CABG‐ineligible patients. Composite events within 1 year after PCI occurred in 55 (4.1%), 91 (7.0%), and 41 (14.8%) of patients in the PCI‐recommended, CABG‐refusal, and CABG‐ineligible groups, respectively. After multivariable adjustment, the risk of the primary composite outcome was significantly higher in the CABG‐refusal (hazard ratio [HR], 1.67 [95% CI, 1.08–3.56]; P=0.02) and CABG‐ineligible patients (HR, 3.26 [95% CI, 1.28–3.65]; P=0.004) groups compared with the reference PCI‐recommended group, driven by increased death and stroke. Conclusions Cardiovascular event rates after PCI were significantly higher in patients with multivessel disease who declined or were ineligible for CABG. Our findings provide real‐world data to inform shared decision‐making discussions.

BackgroundA more sustainable dairy cow diet was designed that minimizes use of feed components digestible by monogastric animals by increasing the quantity of forages.ObjectivesThis study determined if feeding lactating cows the more sustainable, low-starch and high-fiber (LSHF) diet was associated with changes in raw milk microbiota composition and somatic cell count (SCC).MethodsIn a crossover design, 76 lactating Holstein cows were assigned to an LSHF diet or a high-starch and low-fiber (HSLF) diet, similar to common dairy cow diets in the United States, for 10 wk then placed on the opposite diet for 10 wk. The LSHF diet contained greater quantities of forages, beet pulp, and corn distillers' grain, but contained less canola meal and no high-moisture corn compared with the HSLF diet. Raw milk samples were collected from each cow 4-5 d before intervention and 5 wk into each diet treatment. Within 4 d, additional milk samples were collected for measurement of SCC using Fossmatic 7. The microbial community was determined by sequencing the 16S rRNA gene V4-V5 region and analyzing sequences with QIIME2. After quality filtering, 53 cows remained.ResultsRaw milk microbial communities differed by diet and time. Taxa associated with fiber consumption, such as Lachnospiraceae, Lactobacillus, Bacteroides, and Methanobrevibacter, were enriched with the LSHF diet. Meanwhile, taxa associated with mastitis, such as Pseudomonas, Stenotrophomonas, and Enterobacteriaceae, were enriched with the HSLF diet. Relatedly, an interaction of diet and time was found to impact SCC.ConclusionsIn raw milk, consumption of an LSHF diet compared with an HSLF diet was associated with changes in abundance of microbes previously associated with fiber consumption, udder health, and milk spoilage. Further research is needed to determine if an LSHF diet indeed leads to lower rates of mastitis and milk spoilage, which could benefit the dairy industry.

BackgroundBovine milk oligosaccharides (BMOs) have several demonstrated and hypothesized benefits including roles in cognitive development and antipathogenic activities, making them promising ingredients for infant formulas and nutraceutical applications. BMO extraction from bovine milk is challenged by low concentrations relative to nonbioactive simple sugars like lactose. BMO abundances are known to vary with a cow's lactation stage, breed, and parity, but these characteristics are difficult to modify in existing dairy herds. In contrast, diet modification is an accessible target, and is already known to influence milk yield, lipid content, protein levels, and monosaccharide compositions.ObjectivesTo determine the impact of a low starch high fiber versus a high starch low fiber diet on overall BMO profiles and individual BMO abundances in Holstein dairy cattle.MethodsMilk samples were collected from 59 midlactation Holsteins in a crossover study featuring dietary modification with either a low starch high fiber or high starch low fiber feed. BMO profiles were evaluated by nano-LC quadrupole time-of-flight tandem MS, and differences in BMO abundances between diets were evaluated using linear mixed effects modeling.ResultsA total of 19 BMOs were identified across the sample set, including 4 large fucosylated compounds. Seven BMOs were found to have significantly more positive percent changes in yield-adjusted abundance from the pre-experiment baseline period for milk samples collected during feeding with the low starch high fiber diet compared with the high starch low fiber diet.ConclusionsConsuming the low starch high fiber diet promoted greater overall BMO production than the high starch low fiber diet in a population of midlactation Holsteins. Additionally, this study afforded the opportunity to investigate the impact of other factors potentially influencing BMO abundances, furthering understanding of how dairy herd management practices can positively impact milk composition and support the potential use of BMOs as functional ingredients.

BackgroundComputerized methodologies standardize the myocardial perfusion imaging (MPI) interpretation process.MethodsTo develop an automated relative perfusion quantitation approach for 18F-flurpiridaz, PET MPI studies from all phase III trial participants of 18F-flurpiridaz were divided into 3 groups. Count distributions were obtained in N = 40 normal patients undergoing pharmacological or exercise stress. Then, N = 90 additional studies were selected in a derivation group. Following receiver operating characteristic curve analysis, various standard deviations below the mean normal were used as cutoffs for significant CAD, and interobserver variability determined. Finally, diagnostic performance was compared between blinded visual readers and blinded derivations of automated relative quantitation in the remaining N = 548 validation patients.ResultsBoth approaches yielded comparable accuracies for the detection of global CAD, reaching 71% and 72% by visual reads, and 72% and 68% by automated relative quantitation, when using CAD ≥ 70% or ≥ 50% stenosis for significance, respectively. Similar results were observed when analyzing individual coronary territories. In both pharmacological and exercise stress, automated relative quantitation demonstrated significantly more interobserver agreement than visual reads.ConclusionsOur automated method of 18F-flurpiridaz relative perfusion analysis provides a quantitative, objective, and highly reproducible assessment of PET MPI in normal and CAD subjects undergoing either pharmacological or exercise stress.

Video 1Narration of case and demonstration of overture-mediated lumen-apposing metal stent placement for removal of retained capsule endoscopy.

We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59-0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61-1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma.SignificanceAdjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587.

Argumentation is an important component of scientific education (Osborne, 2010). However, how students create and evaluate competing arguments in scientific investigations is a complex construct, which presents significant challenges for assessment. We engaged 349 middle and high school students in a virtual scientific investigation based on an authentic problem involving the ecosystem of Yellowstone National Park. Students evaluated three possible causes for vegetation loss in Lamar Valley: tourism, global warming, and killing wolves. Students compared their responses to individual claims to formulate a final decision. The authors developed a coding system to assess student arguments and analysed how students changed their evaluations across the investigation. Four distinct levels of responses reveal the range of student decision making and patterns that have implications for instruction and assessment. Few student evaluations explained both merits and weaknesses of claims.