Dupilumab reduces systemic corticosteroid use and sinonasal surgery rate in CRSwNP.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease with a high symptom burden and poor quality of life. Treatment options include recurrent surgeries and/or frequent systemic corticosteroids (SCS). Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2-mediated inflammation. We report results of pooled analyses from 2 randomised, double-blind, placebo-controlled phase 3 studies (SINUS 24 [NCT02912468]; SINUS-52 [NCT02898454]) to evaluate dupilumab effect versus placebo in adults with CRSwNP with/without SCS use and sinonasal surgery. METHODOLOGY: SINUS-24 patients were randomised 1:1 to subcutaneous dupilumab 300 mg (n=143) or placebo (n=133) every 2 weeks (q2w) for 24 weeks. SINUS-52 patients were randomised 1:1:1 to 52 weeks of subcutaneous dupilumab 300 mg q2w (n=150), 24 weeks q2w followed by 28 weeks of dupilumab 300 mg every 4 weeks (n=145) or 52 weeks of placebo q2w (n=153). RESULTS: Dupilumab reduced the number of patients undergoing sinonasal surgery (82.6%), the need for in-study SCS use (73.9%), and SCS courses (75.3%). Significant improvements were observed with dupilumab vs placebo regardless of prior sinonasal surgery or SCS use in nasal polyp, nasal congestion, Lund-MacKay, and Sinonasal Outcome Test (22-items) scores, and the University of Pennsylvania Smell Identification Test. CONCLUSIONS: Dupilumab demonstrated significant improvements in disease signs and symptoms and reduced the need for sino-nasal surgery and SCS use versus placebo in patients with severe CRSwNP, regardless of SCS use in the previous 2 years, or prior sinonasal surgery.

Circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-binding protein-3, genetic polymorphisms and mammographic density in premenopausal Mexican women: results from the ESMaestras cohort.

The insulin-like growth factor (IGF) axis plays an essential role in the development of the mammary gland. High circulating levels of IGF-I and of its major binding protein IGFBP3 have been related with increased mammographic density in Caucasian premenopausal women. Some common single nucleotide polymorphisms (SNPs) in genes of the IGF pathway have also been suggested to play a role in mammographic density. We conducted a cross-sectional study nested within the large Mexican ESMaestras cohort to investigate the relation between circulating levels of IGF-I, IGFBP-3, the IGF-I/IGFBP-3 ratio, five common SNPs in the IGF-1, IGFBP-3 and IGF-1R genes and mammographic density in 593 premenopausal Mexican women. Mean age at mammogram was 43.1 (standard deviation, SD = 3.7) years, and average body mass index (BMI) at recruitment was 28.5 kg/m(2). Mean percent mammographic density was 36.5% (SD: 17.1), with mean dense tissue area of 48.3 (SD: 33.3) cm(2) . Mean IGF-I and IGFBP-3 concentrations were 15.33 (SD: 5.52) nmol/l and 114.96 (SD: 21.34) nmol/l, respectively. No significant associations were seen between percent density and biomarker concentrations, but women with higher IGF-I and IGF-I/IGFBP-3 concentrations had lower absolute dense (p(trend) = 0.03 and 0.09, respectively) and nondense tissue areas (p(trend) < 0.001 for both parameters). However, these associations were null after adjustment by BMI. SNPs in specific genes were associated with circulating levels of growth factors, but not with mammographic density features. These results do not support the hypothesis of a strong association between circulating levels of growth hormones and mammographic density in Mexican premenopausal women.

Aqueously altered igneous rocks sampled on the floor of Jezero crater, Mars.

The Perseverance rover landed in Jezero crater, Mars, to investigate ancient lake and river deposits. We report observations of the crater floor, below the crater's sedimentary delta, finding that the floor consists of igneous rocks altered by water. The lowest exposed unit, informally named Séítah, is a coarsely crystalline olivine-rich rock, which accumulated at the base of a magma body. Magnesium-iron carbonates along grain boundaries indicate reactions with carbon dioxide-rich water under water-poor conditions. Overlying Séítah is a unit informally named Máaz, which we interpret as lava flows or the chemical complement to Séítah in a layered igneous body. Voids in these rocks contain sulfates and perchlorates, likely introduced by later near-surface brine evaporation. Core samples of these rocks have been stored aboard Perseverance for potential return to Earth.

Pre-Flight Calibration of the Mars 2020 Rover Mastcam Zoom (Mastcam-Z) Multispectral, Stereoscopic Imager.

The NASA Perseverance rover Mast Camera Zoom (Mastcam-Z) system is a pair of zoomable, focusable, multi-spectral, and color charge-coupled device (CCD) cameras mounted on top of a 1.7 m Remote Sensing Mast, along with associated electronics and two calibration targets. The cameras contain identical optical assemblies that can range in focal length from 26 mm ( 25.5 ∘ × 19.1 ∘ FOV ) to 110 mm ( 6.2 ∘ × 4.2 ∘ FOV ) and will acquire data at pixel scales of 148-540 µm at a range of 2 m and 7.4-27 cm at 1 km. The cameras are mounted on the rover's mast with a stereo baseline of 24.3 ± 0.1  cm and a toe-in angle of 1.17 ± 0.03 ∘ (per camera). Each camera uses a Kodak KAI-2020 CCD with 1600 × 1200 active pixels and an 8 position filter wheel that contains an IR-cutoff filter for color imaging through the detectors' Bayer-pattern filters, a neutral density (ND) solar filter for imaging the sun, and 6 narrow-band geology filters (16 total filters). An associated Digital Electronics Assembly provides command data interfaces to the rover, 11-to-8 bit companding, and JPEG compression capabilities. Herein, we describe pre-flight calibration of the Mastcam-Z instrument and characterize its radiometric and geometric behavior. Between April 26 t h and May 9 t h , 2019, ∼45,000 images were acquired during stand-alone calibration at Malin Space Science Systems (MSSS) in San Diego, CA. Additional data were acquired during Assembly Test and Launch Operations (ATLO) at the Jet Propulsion Laboratory and Kennedy Space Center. Results of the radiometric calibration validate a 5% absolute radiometric accuracy when using camera state parameters investigated during testing. When observing using camera state parameters not interrogated during calibration (e.g., non-canonical zoom positions), we conservatively estimate the absolute uncertainty to be < 10 % . Image quality, measured via the amplitude of the Modulation Transfer Function (MTF) at Nyquist sampling (0.35 line pairs per pixel), shows MTF Nyquist = 0.26 - 0.50 across all zoom, focus, and filter positions, exceeding the > 0.2 design requirement. We discuss lessons learned from calibration and suggest tactical strategies that will optimize the quality of science data acquired during operation at Mars. While most results matched expectations, some surprises were discovered, such as a strong wavelength and temperature dependence on the radiometric coefficients and a scene-dependent dynamic component to the zero-exposure bias frames. Calibration results and derived accuracies were validated using a Geoboard target consisting of well-characterized geologic samples. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11214-021-00795-x.

The Mars 2020 Perseverance Rover Mast Camera Zoom (Mastcam-Z) Multispectral, Stereoscopic Imaging Investigation.

Mastcam-Z is a multispectral, stereoscopic imaging investigation on the Mars 2020 mission's Perseverance rover. Mastcam-Z consists of a pair of focusable, 4:1 zoomable cameras that provide broadband red/green/blue and narrowband 400-1000 nm color imaging with fields of view from 25.6° × 19.2° (26 mm focal length at 283 µrad/pixel) to 6.2° × 4.6° (110 mm focal length at 67.4 µrad/pixel). The cameras can resolve (≥ 5 pixels) ∼0.7 mm features at 2 m and ∼3.3 cm features at 100 m distance. Mastcam-Z shares significant heritage with the Mastcam instruments on the Mars Science Laboratory Curiosity rover. Each Mastcam-Z camera consists of zoom, focus, and filter wheel mechanisms and a 1648 × 1214 pixel charge-coupled device detector and electronics. The two Mastcam-Z cameras are mounted with a 24.4 cm stereo baseline and 2.3° total toe-in on a camera plate ∼2 m above the surface on the rover's Remote Sensing Mast, which provides azimuth and elevation actuation. A separate digital electronics assembly inside the rover provides power, data processing and storage, and the interface to the rover computer. Primary and secondary Mastcam-Z calibration targets mounted on the rover top deck enable tactical reflectance calibration. Mastcam-Z multispectral, stereo, and panoramic images will be used to provide detailed morphology, topography, and geologic context along the rover's traverse; constrain mineralogic, photometric, and physical properties of surface materials; monitor and characterize atmospheric and astronomical phenomena; and document the rover's sample extraction and caching locations. Mastcam-Z images will also provide key engineering information to support sample selection and other rover driving and tool/instrument operations decisions.

Synergistic Ground and Orbital Observations of Iron Oxides on Mt. Sharp and Vera Rubin Ridge.

Visible/short-wave infrared spectral data from the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) show absorptions attributed to hematite at Vera Rubin ridge (VRR), a topographic feature on northwest Mt. Sharp. The goals of this study are to determine why absorptions caused by ferric iron are strongly visible from orbit at VRR and to improve interpretation of CRISM data throughout lower Mt. Sharp. These goals are achieved by analyzing coordinated CRISM and in situ spectral data along the Curiosity Mars rover's traverse. VRR bedrock within areas that have the deepest ferric absorptions in CRISM data also has the deepest ferric absorptions measured in situ. This suggests strong ferric absorptions are visible from orbit at VRR because of the unique spectral properties of VRR bedrock. Dust and mixing with basaltic sand additionally inhibit the ability to measure ferric absorptions in bedrock stratigraphically below VRR from orbit. There are two implications of these findings: (1) Ferric absorptions in CRISM data initially dismissed as noise could be real, and ferric phases are more widespread in lower Mt. Sharp than previously reported. (2) Patches with the deepest ferric absorptions in CRISM data are, like VRR, reflective of deeper absorptions in the bedrock. One model to explain this spectral variability is late-stage diagenetic fluids that changed the grain size of ferric phases, deepening absorptions. Curiosity's experience highlights the strengths of using CRISM data for spectral absorptions and associated mineral detections and the caveats in using these data for geologic interpretations and strategic path planning tools.

Early resistance to therapy during induction in childhood acute lymphoblastic leukemia.

Many patients with acute lymphoblastic leukemia (ALL) are not cured by current therapy because of the development of drug resistance. It is not clear when resistance develops during the growth of the leukemic clone and whether resistant cells are already present at diagnosis or develop later during treatment. Twenty-two uniformly treated children with ALL were studied throughout induction treatment. The size of the leukemic clone in blood and marrow was estimated by limiting dilution PCR analysis, using the rearranged immunoglobulin heavy chain gene as a molecular marker. The decline in the number of leukemic cells was biphasic in virtually all patients. For both marrow and blood, the logarithmic mean of the number of leukemic cells fell by approximately four orders of magnitude during the first 2 weeks, one order of magnitude during the third week, and not at all during the last two weeks of induction treatment. For marrow, the median of the fraction of leukemic cells in each patient that survived per week of treatment was 0.008 for the first 2 weeks, 0.12 for the third week, and 1.4 for the last 2 weeks; for blood, the corresponding figures were 0.003, 0.14, and 0.69, respectively. In individual patients, the results for marrow and blood showed good correlation. The biphasic decline of leukemic cell number suggests that most leukemic cells were sensitive to treatment and were rapidly killed, leaving behind a minor but substantial population of drug-resistant cells. The most likely explanation for this phenomenon is that these resistant cells were already present at diagnosis, their resistance having originated from genetic or epigenetic mutations during prior growth of the leukemic clone.

The stratigraphy and evolution of lower Mount Sharp from spectral, morphological, and thermophysical orbital data sets.

We have developed a refined geologic map and stratigraphy for lower Mount Sharp using coordinated analyses of new spectral, thermophysical, and morphologic orbital data products. The Mount Sharp group consists of seven relatively planar units delineated by differences in texture, mineralogy, and thermophysical properties. These units are (1-3) three spatially adjacent units in the Murray formation which contain a variety of secondary phases and are distinguishable by thermal inertia and albedo differences, (4) a phyllosilicate-bearing unit, (5) a hematite-capped ridge unit, (6) a unit associated with material having a strongly sloped spectral signature at visible near-infrared wavelengths, and (7) a layered sulfate unit. The Siccar Point group consists of the Stimson formation and two additional units that unconformably overlie the Mount Sharp group. All Siccar Point group units are distinguished by higher thermal inertia values and record a period of substantial deposition and exhumation that followed the deposition and exhumation of the Mount Sharp group. Several spatially extensive silica deposits associated with veins and fractures show that late-stage silica enrichment within lower Mount Sharp was pervasive. At least two laterally extensive hematitic deposits are present at different stratigraphic intervals, and both are geometrically conformable with lower Mount Sharp strata. The occurrence of hematite at multiple stratigraphic horizons suggests redox interfaces were widespread in space and/or in time, and future measurements by the Mars Science Laboratory Curiosity rover will provide further insights into the depositional settings of these and other mineral phases.

Large wind ripples on Mars: A record of atmospheric evolution.

Wind blowing over sand on Earth produces decimeter-wavelength ripples and hundred-meter- to kilometer-wavelength dunes: bedforms of two distinct size modes. Observations from the Mars Science Laboratory Curiosity rover and the Mars Reconnaissance Orbiter reveal that Mars hosts a third stable wind-driven bedform, with meter-scale wavelengths. These bedforms are spatially uniform in size and typically have asymmetric profiles with angle-of-repose lee slopes and sinuous crest lines, making them unlike terrestrial wind ripples. Rather, these structures resemble fluid-drag ripples, which on Earth include water-worked current ripples, but on Mars instead form by wind because of the higher kinematic viscosity of the low-density atmosphere. A reevaluation of the wind-deposited strata in the Burns formation (about 3.7 billion years old or younger) identifies potential wind-drag ripple stratification formed under a thin atmosphere.

Comparison of methods for assessment of minimal residual disease in childhood B-lineage acute lymphoblastic leukemia.

The level of minimal residual disease (MRD) early in treatment of acute lymphoblastic leukemia (ALL) strongly predicts the risk of marrow relapse. As a variety of methods of varying complexity have been separately used for detecting and quantifying MRD, we compared the prognostic utility of three methods measurement of blast percentage on day 14 of treatment, detection of monoclonality on day 14 or day 35, and measurement of MRD by PCR-based limiting dilution analysis on day 14 or day 35. The study group comprised 38 children aged 1-15 with Philadelphia-negative B-lineage ALL who were uniformly treated and followed until relapse or for a minimum of 5 years. We also studied some of the technical factors which influence the ability to detect MRD. Measurement of blast percentage on day 14 by an expert morphologist, detection of monoclonality on day 35, and PCR-based measurement of MRD levels on days 14 and 35 all showed significant ability to divide patients into prognostic groups. Measurement of blast percentage on day 14 by routine morphology or detection of monoclonality on day 14 were not useful. The quality of DNA samples varied greatly, as determined by amplifiability in the PCR. However, virtually all amplifiable leukemic targets in a sample were detectable which suggests that the level of detection achieved by limiting dilution analysis is essentially determined by the amount of DNA which it is practicable to study. We conclude that quantification of MRD at the end of induction provides the full range of prognostic information for marrow relapse but is complex; detection of monoclonality on day 35 is simple and has good positive predictive value; and quantification of MRD on day 14 merits further study. PCR-based methods for measurement of MRD levels should incorporate a correction for variation in DNA amplifiability.

Metastatic osteogenic sarcoma to the heart presenting as bacterial endocarditis.

A patient with metastatic osteogenic sarcoma involving the left atrium is described who presented with features of bacterial endocarditis. The source of infection was the adjacent esophagus into which the tumor had eroded. This case demonstrates that sarcomas metastasizing to the heart may result in a clinical condition indistinguishable from infective endocarditis. At post-mortem, careful dissection of cardiac metastases should be undertaken to check for possible esophageal involvement.

Leiomyosarcoma of the saphenous vein in a child with 12-year follow-up.

Leiomyosarcomas of the vasculature are exceedingly rare tumors in childhood. The case of a 2-year-old girl who underwent three local excisions with two courses of adjuvant chemotherapy over 3 years for a leiomyosarcoma of a saphenous vein tributary is described. Follow-up over the following 9 years has shown no evidence of further recurrence or metastases suggesting that cure has been achieved. Treatment options are discussed and pertinent literature is reviewed.

Perceived risk as a constraint on occupational performance during hot and cold water pouring.

OBJECTIVE: Occupational therapists are interested in quality of movement under different environmental conditions. It has been shown that during reaching tasks, the physical aspects of the objects to be grasped can influence the quality of movement. This study investigated whether perceived risk (water temperature) affected the quality of movement during a pouring task. METHOD: In a counterbalanced, repeated measures design, 56 participants (M = 27.1 years, SD = 7.4 years) poured hot, then cold water to prepare hot and cold beverages. Dependent variables included movement time, displacement, peak velocity, percentage of movement time to peak velocity, and movement units. Data were analyzed with paired t tests. RESULTS: Participant performance in displacement and movement time was significantly different when considering the entire pouring task for both the hot and the cold conditions (ps < .05). In addition, significant differences were found in the discrete movement "sub-portions" of the pouring task (ps < .05). CONCLUSION: Perceived risk is an element of meaning that the occupational therapist can consider in providing the person with just enough challenge to facilitate successful performance. By varying the amount of perceived risk in the occupational form, the therapist can help the person experience and develop the range of movement strategies required by everyday occupations. Future research is needed to corroborate these findings in simple and more complex occupations as well as to examine perceived risk in special populations.

The effect of contextual relevance on motor skill transfer.

OBJECTIVE: The purpose of this study was to investigate whether practicing a complex self-care occupation in a contextually relevant environment would enhance the learning and transfer of skill. METHOD: The design consisted of an acquisition phase, a rest period, and a transfer phase. Fifty-six women were recruited for this study and randomly assigned to one of three groups: (a) a contextually relevant (CR) group that practiced tying a necktie knot onto a mannequin, (b) a non-contextually relevant (NCR) group that practiced tying the same type of knot with a rope onto a wooden pole, and (c) a control group that did not practice at all during the acquisition phase. Participants in all three groups tied a necktie onto themselves during the transfer phase. Dependent variables were movement time, movement units, and the quality of the necktie knot. RESULTS: No difference in the rate of performance change was found during the acquisition phase between the CR and NCR groups. The difference among the CR, NCR, and control groups' initial transfer phase performance was near significance for movement time and movement units. A significant difference in the rate of performance change was found among the three groups in movement time and movement units during the transfer phase but not in the quality of necktie knot measures. CONCLUSION: The degree of similarity during the acquisition of a dressing skill may influence the rate of performance improvement in a similar dressing skill during a transfer phase. Until further research has been established, generalization of these results to special populations should be done conservatively.

Cross-transfer effects in the upper extremity during an occupationally embedded exercise.

OBJECTIVE: Cross-transfer effects were investigated during an occupationally embedded task that involved learning a fine motor skill. Cross-transfer is a phenomenon that occurs when an untrained limb receives some of the same benefits in performance from unilateral training that the contralateral limb received. It was hypothesized that cross-transfer would occur after a unilateral training regime using an occupationally embedded task. METHOD: Forty-eight participants (mean age = 24.4 years) volunteered for this repeated-measures study. Participants were randomly assigned to a training or control group and were asked to complete a toy maze with their right and left hands for the pretest and posttest. Whereas participants in the control group did not train, participants in the training group completed a toy maze three times a day for 7 days with their left hands. All participants returned in 1 week to complete the posttest portion of the experiment. Dependent variables included movement time, movement units, force oscillations, and average force. RESULTS: Significant decreases in movement time and force oscillations were found for the untrained limbs (p < .0125) in the training group. No significant differences were found in movement units or average force. The improved movement time and force oscillations in the untrained limb provides evidence suggesting that cross-transfer occurred. CONCLUSION: This study indicates that with a population without impairments, cross-transfer can occur during an occupationally embedded task. This phenomenon may prove useful to the field of occupational therapy to rehabilitate immobilized extremities. Further research is needed to test this phenomenon with special populations.

Grip strengths and required forces in accessing everyday containers in a normal population.

OBJECTIVE: A commonly adhered to operating principle in occupational therapy clinics is that a person must exhibit 20 lb of grip strength before his or her hand is considered "functional." This study examined the relationship between hand and finger grip performances with the forces required to open common household containers. METHOD: The grip and pinch strengths of 49 college students were obtained using dynamometry. The forces required to open six common household containers were measured using Force Sensing Resistors attached to each container. RESULTS: Weak correlations were found (r = -.179 to r = .333) between grip and pinch strength performances and the forces used to operate the accessing mechanisms of the containers. Analyses of variances demonstrated significantly greater grip and pinch strength performances in men than in women (ps < .05) but no significant difference between the genders in the forces generated to open the containers (ps > .05). CONCLUSIONS: In a normal population of college students, the premise that greater hand strength affords greater performance in accessing everyday household containers was not supported. Implications suggest that grip and pinch dynamometry are not conclusive evaluative tools for predicting hand function while opening a select group of containers. The relationship between traditional dynamometry and hand performance during a variety of functional tasks needs to be examined in clinical populations as well.

Elemental geochemistry of sedimentary rocks at Yellowknife Bay, Gale crater, Mars.

Sedimentary rocks examined by the Curiosity rover at Yellowknife Bay, Mars, were derived from sources that evolved from an approximately average martian crustal composition to one influenced by alkaline basalts. No evidence of chemical weathering is preserved, indicating arid, possibly cold, paleoclimates and rapid erosion and deposition. The absence of predicted geochemical variations indicates that magnetite and phyllosilicates formed by diagenesis under low-temperature, circumneutral pH, rock-dominated aqueous conditions. Analyses of diagenetic features (including concretions, raised ridges, and fractures) at high spatial resolution indicate that they are composed of iron- and halogen-rich components, magnesium-iron-chlorine-rich components, and hydrated calcium sulfates, respectively. Composition of a cross-cutting dike-like feature is consistent with sedimentary intrusion. The geochemistry of these sedimentary rocks provides further evidence for diverse depositional and diagenetic sedimentary environments during the early history of Mars.

Ancient impact and aqueous processes at Endeavour Crater, Mars.

The rover Opportunity has investigated the rim of Endeavour Crater, a large ancient impact crater on Mars. Basaltic breccias produced by the impact form the rim deposits, with stratigraphy similar to that observed at similar-sized craters on Earth. Highly localized zinc enrichments in some breccia materials suggest hydrothermal alteration of rim deposits. Gypsum-rich veins cut sedimentary rocks adjacent to the crater rim. The gypsum was precipitated from low-temperature aqueous fluids flowing upward from the ancient materials of the rim, leading temporarily to potentially habitable conditions and providing some of the waters involved in formation of the ubiquitous sulfate-rich sandstones of the Meridiani region.