Axicabtagene ciloleucel (axi-cel) was approved by the Food and Drug Administration for relapsed aggressive B-cell non-Hodgkin lymphoma in part on the basis of durable remission rates of approximately ...40% in a clinical trial population. Whether this efficacy, and the rates of toxicity, would be consistent in a postcommercial setting, with relaxed eligibility criteria and bridging therapy, is unknown. This study describes the efficacy and safety correlates and outcomes in this setting.
One hundred twenty-two patients from 7 medical centers in the United States were treated with axi-cel and were included in a modified intent-to-treat (mITT) analysis. Seventy-six patients (62%) were ineligible for the ZUMA-1 trial. Response and toxicity rates, duration of response (DOR), survival, and covariates are described on the basis of the mITT population. Correlative studies on blood and tumor samples were performed to investigate potential biomarkers of response and resistance.
Median follow-up was 10.4 months. In the mITT population, the best overall and complete response (CR) rates were 70% and 50%, respectively. Median DOR and progression-free survival (PFS) were 11.0 and 4.5 months in all patients and were not reached (NR) in CR patients. Median overall survival (OS) was NR; 1-year OS was 67% (95% CI, 59% to 77%). Although response rates were similar in the ZUMA-1-eligible and ZUMA-1-ineligible groups (70%
68%), there was a statistically significant improvement in CR rate (63%
42%,
= .016), DOR (median, NR
5.0 months;
= .014), PFS (median, NR
3.3 months;
= .020), and OS (1-year OS, 89%
54%;
< .001) in patients who were ZUMA-1 eligible. Rates of grade ≥ 3 cytokine release syndrome and neurotoxicty were 16% and 35%, respectively.
Axi-cel yields similar rates of overall response and toxicity in commercial and trial settings, although CR rates and DOR were more favorable in patients eligible for ZUMA-1.
Sequence polymorphisms in a 58-kilobase (kb) interval on chromosome 9p21 confer a markedly increased risk of coronary artery disease (CAD), the leading cause of death worldwide. The variants have a ...substantial effect on the epidemiology of CAD and other life-threatening vascular conditions because nearly one-quarter of Caucasians are homozygous for risk alleles. However, the risk interval is devoid of protein-coding genes and the mechanism linking the region to CAD risk has remained enigmatic. Here we show that deletion of the orthologous 70-kb non-coding interval on mouse chromosome 4 affects cardiac expression of neighbouring genes, as well as proliferation properties of vascular cells. Chr4 70kb/ 70kb mice are viable, but show increased mortality both during development and as adults. Cardiac expression of two genes near the non-coding interval, Cdkn2a and Cdkn2b, is severely reduced in chr4 70kb/ 70kb mice, indicating that distant-acting gene regulatory functions are located in the non-coding CAD risk interval. Allele-specific expression of Cdkn2b transcripts in heterozygous mice showed that the deletion affects expression through a cis-acting mechanism. Primary cultures of chr4 70kb/ 70kb aortic smooth muscle cells exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis. Taken together, our results provide direct evidence that the CAD risk interval has a pivotal role in regulation of cardiac Cdkn2a/b expression, and suggest that this region affects CAD progression by altering the dynamics of vascular cell proliferation.
Although sentences unfold sequentially, one word at a time, most linguistic theories propose that their underlying syntactic structure involves a tree of nested phrases rather than a linear sequence ...of words. Whether and how the brain builds such structures, however, remains largely unknown. Here, we used human intracranial recordings and visual word-by-word presentation of sentences and word lists to investigate how left-hemispheric brain activity varies during the formation of phrase structures. In a broad set of language-related areas, comprising multiple superior temporal and inferior frontal sites, high-gamma power increased with each successive word in a sentence but decreased suddenly whenever words could be merged into a phrase. Regression analyses showed that each additional word or multiword phrase contributed a similar amount of additional brain activity, providing evidence for amerge operation that applies equally to linguistic objects of arbitrary complexity. More superficial models of language, based solely on sequential transition probability over lexical and syntactic categories, only captured activity in the posterior middle temporal gyrus. Formal model comparison indicated that the model of multiword phrase construction provided a better fit than probability-based models at most sites in superior temporal and inferior frontal cortices. Activity in those regions was consistent with a neural implementation of a bottom-up or left-corner parser of the incoming language stream. Our results provide initial intracranial evidence for the neurophysiological reality of the merge operation postulated by linguists and suggest that the brain compresses syntactically well-formed sequences of words into a hierarchy of nested phrases.
The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal ...adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient’s primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.
Indicators of landscape condition should be sensitive and specific to environmental change and provide early warning detection of ncipient changes. We assessed a suite of five spectral metrics ...derived from Landsat 5 TM imagery spanning a decade (1996–2007) to quantify ecosystem condition in the ridge-slough mosaic of the Everglades (South Florida, USA). These included the normalized difference vegetation index (NDVI), the same index using green instead of red band as the visible reference (NDVIg), the normalized difference water index (NDWI), the simple ratio of NIR and red bands (SR) and the moisture stress index (MSI). Mean and variance from pure ridge or slough pixels (i.e., those >30 m from a mapped patch edge) were quantified for twentyfour 2 × 5 km blocks across a gradient of hydrologic and ecological condition. Metrics were compared with field measures of landscape condition from block-scale soil elevation surveys, which capture dramatic spatial gradients between conserved and degraded locations. Elevationbased measures of landscape condition, validated as diagnostic in previous work, included soil elevation bi-modality (BISE), a binary measure of ecosystem condition, and the soil elevation standard deviation (SDSE), a continuous measure of condition. Spectral metric performance was assessed based on the strength (sensitivity) and shape (leading vs.lagging) of the relationship with elevation-based measures. We observed significant logistic regression slopes with BISE for only 3 metrics (mean ridge NDVI and NDVIg, mean ridge SR). In prediction of variance SDSE, the standard deviation of our VIs was more informative than the mean, and measures from sloughs more informative than ridges. The strongest predictions are variance in slough NDVIg and SR, suggesting that spatial heterogeneity in slough biomass is most informative for predicting the status of soil elevation variance. None of the vegetation metrics were leading indicators of change; a multivariate model using three VIs selected based on consistent performance across years (variance in Slough SR, slough NDVIg, and ridge NDWI) substantially improve predictions of SDSE and yielded more plausible prediction maps. These findings suggest that soil elevation changes from altered peat accretion dynamics precede visible changes in vegetation reflectance. While this constrains predictions of incipient ecosystem change, the reasonable performance of spectral metrics indicates that efficient monitoring of ridge-slough landscape health is possible as part of the ongoing Everglades restoration effort.
•Spectral metrics can diagnose the spatial extent and severity of ecological change.•Most metrics are lagging indicators, indicating poor early warning detection.•Multivariate models outperformed univariate models for predicting degradation.
Geographically isolated wetlands (GIWs), those surrounded by uplands, exchange materials, energy, and organisms with other elements in hydrological and habitat networks, contributing to landscape ...functions, such as flow generation, nutrient and sediment retention, and biodiversity support. GIWs constitute most of the wetlands in many North American landscapes, provide a disproportionately large fraction of wetland edges where many functions are enhanced, and form complexes with other water bodies to create spatial and temporal heterogeneity in the timing, flow paths, and magnitude of network connectivity. These attributes signal a critical role for GIWs in sustaining a portfolio of landscape functions, but legal protections remain weak despite preferential loss from many landscapes. GIWs lack persistent surface water connections, but this condition does not imply the absence of hydrological, biogeochemical, and biological exchanges with nearby and downstream waters. Although hydrological and biogeochemical connectivity is often episodic or slow (e.g., via groundwater), hydrologic continuity and limited evaporative solute enrichment suggest both flow generation and solute and sediment retention. Similarly, whereas biological connectivity usually requires overland dispersal, numerous organisms, including many rare or threatened species, use both GIWs and downstream waters at different times or life stages, suggesting that GIWs are critical elements of landscape habitat mosaics. Indeed, weaker hydrologic connectivity with downstream waters and constrained biological connectivity with other landscape elements are precisely what enhances some GIW functions and enables others. Based on analysis of wetland geography and synthesis of wetland functions, we argue that sustaining landscape functions requires conserving the entire continuum of wetland connectivity, including GIWs.
Abstract
In late 2021, the Omicron SARS-CoV-2 variant overtook the previously dominant Delta variant, but the extent to which this transition was driven by immune evasion or a change in the inherent ...transmissibility is currently unclear. We estimate SARS-CoV-2 transmission within Danish households during December 2021. Among 26,675 households (8,568 with the Omicron VOC), we identified 14,140 secondary infections within a 1–7-day follow-up period. The secondary attack rate was 29% and 21% in households infected with Omicron and Delta, respectively. For Omicron, the odds of infection were 1.10 (95%-CI: 1.00-1.21) times higher for unvaccinated, 2.38 (95%-CI: 2.23-2.54) times higher for fully vaccinated and 3.20 (95%-CI: 2.67-3.83) times higher for booster-vaccinated contacts compared to Delta. We conclude that the transition from Delta to Omicron VOC was primarily driven by immune evasiveness and to a lesser extent an inherent increase in the basic transmissibility of the Omicron variant.
Background:
The incidence of upper extremity injuries in baseball pitchers is increasing. Over the past decade, research has attempted to elucidate the cause of these injuries, focusing mainly on ...pitching arm mechanics with little examination of other important segments, such as the trunk. This is surprising, as trunk motion has been shown to have significant effects on pitching mechanics.
Purpose:
To determine the associations between trunk rotation, ball velocity, and the moments about the elbow joint.
Study Design:
Descriptive laboratory study.
Methods:
Data collected using 3-dimensional motion analysis techniques from 99 collegiate pitchers (18.0-24.8 years) were analyzed. A random intercept mixed-effects regression model was used to determine if significant associations existed between trunk rotation and ball velocity or elbow varus moment.
Results:
Significant associations were found between trunk rotation angle at ball release and elbow varus moment (P = .019, β = 0.254) as well as ball velocity (P = .016, β = 0.060). For every 10° increase over the average trunk rotation angle at ball release, the elbow varus moment increased by 2.54 N·m and the ball velocity increased by 0.60 m/s. Additionally, the maximum rotational velocity of the trunk was positively associated with elbow varus moment (P < .001, β = 0.029) and ball velocity (P < .001, β = 0.007). For every 100 deg/s increase over the average maximum rotational velocity of the trunk, the elbow varus moment increased by 2.90 N·m and the ball velocity increased by 0.70 m/s.
Conclusion:
In collegiate pitchers, trunk rotation angle at ball release was significantly associated with ball velocity and elbow varus moment. Also, an increase in maximum rotational velocity of the trunk was significantly associated with an increase in the ball velocity and elbow varus moment. This work demonstrates the importance of trunk mechanics in the kinetic chain of the pitch cycle.
Clinical Relevance:
Pitching coaches and trainers can use the results to stress the importance of trunk mechanics in pitching, specifically, combining adequate core function with increased trunk rotational velocity in an effort to increase pitching velocity without increasing elbow joint stress.
The mechanisms driving catchment nitrogen storage and release operate at multiple spatiotemporal scales. Consequently, analyses grounded in different observational timescales can yield discrepant ...interpretations of underlying mechanisms. To assess the consistency of nitrate export patterns between event‐ and inter‐annual scales, we evaluated multiple years of high‐frequency observations of nitrate concentrations (C) and discharge (Q) including 3,480 discrete discharge events from 28 dominantly agricultural catchments. We observed consistent and often drastic divergence between long‐term and median event‐specific C‐Q patterns. Most catchments showed long‐term enrichment patterns (positive C‐Q slope), but events were, on average, more chemostatic (close‐to‐zero C‐Q slopes). C‐Q slope variability was high for small events but decreased with event magnitude, approaching chemostatic patterns during the largest storms, yielding compelling evidence against nitrate source limitation. We conclude that nitrate export patterns observed at different temporal scales and event magnitudes are controlled by different processes, therefore embedding complementary information.
Plain Language Summary
Storage and mobilization of nitrogen in the landscape ultimately shape nitrate concentration dynamics in streams and their transport to downstream receiving waters. However, the temporal resolution of data analyses (e.g., long‐term or high‐flow events) can affect the interpretation of nitrate export from catchments and underlying mechanisms. To test whether nitrate export patterns differ between event and long‐term time scales, we evaluated several years of daily observations of nitrate concentration and discharge, including 3,480 high‐flow events from 28 dominantly agricultural catchments. We observed consistent and often drastic divergence between long‐term and average event‐specific export patterns. The variability in export patterns between events decreased with event magnitude toward patterns that indicate no nitrogen source limitation. Nitrate export patterns are regulated by different controls depending on the temporal scale of analysis, which must be considered to avoid incomplete and misleading interpretations about the underlying mechanisms.
Key Points
Long‐term and event‐scale nitrate export patterns diverge, pointing at complementary drivers of catchment functioning across time scales
Event‐scale C‐Q slopes decreased in variability with event magnitude and showed no signs of source limitation at high‐magnitude events
Multi‐catchment high‐frequency data revealed the crucial role of time scale and event magnitude for interpreting nitrate export patterns
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