ABSTRACT We present the first dust emission results toward a sample of seven protostellar disk candidates around Class 0 and I sources in the Perseus molecular cloud from the VLA Nascent Disk and ...Multiplicity (VANDAM) survey with ∼0 05 or 12 AU resolution. To examine the surface brightness profiles of these sources, we fit the Ka-band 8 mm dust-continuum data in the u, v-plane to a simple, parametrized model based on the Shakura-Sunyaev disk model. The candidate disks are well-fit by a model with a disk-shaped profile and have masses consistent with known Class 0 and I disks. The inner-disk surface densities of the VANDAM candidate disks have shallower density profiles compared to disks around more evolved Class II systems. The best-fit model radii of the seven early-result candidate disks are Rc > 10 AU; at 8 mm, the radii reflect lower limits on the disk size since dust continuum emission is tied to grain size and large grains radially drift inwards. These relatively large disks, if confirmed kinematically, are inconsistent with theoretical models where the disk size is limited by strong magnetic braking to <10 AU at early times.
We introduce tensor-network stabilizer codes which come with a natural tensor-network decoder. These codes can correspond to any geometry, but, as a special case, we generalize holographic codes ...beyond those constructed from perfect or block-perfect isometries, and we give an example that corresponds to neither. Using the tensor-network decoder, we find a threshold of 18.8% for this code under depolarizing noise. We show that, for holographic codes, the exact tensor-network decoder (with no bond-dimension truncation) has polynomial complexity in the number of physical qubits, even for locally correlated noise, making this the first efficient decoder for holographic codes against Pauli noise and, also, a rare example of a decoder that is both efficient and exact.
OBJECTIVE: This study examined the association between objectively measured sedentary activity and metabolic syndrome among older adults. RESEARCH DESIGN AND METHODS: Data were from 1,367 men and ...women, aged ≥60 years who participated in the 2003-2006 National Health and Nutrition Examination Survey (NHANES). Sedentary time during waking hours was measured by an accelerometer (<100 counts per minute). A sedentary bout was defined as a period of time >5 min. A sedentary break was defined as an interruption in sedentary time (≥100 counts per minute). Metabolic syndrome was defined according to the Adult Treatment Panel (ATP) III criteria. RESULTS: On average, people spent 9.5 h (65% of wear time) as sedentary. Compared with people without metabolic syndrome, people with metabolic syndrome spent a greater percentage of time as sedentary (67.3 vs. 62.2%), had longer average sedentary bouts (17.7 vs. 16.7 min), had lower intensity during sedentary time (14.8 vs. 15.8 average counts per minute), and had fewer sedentary breaks (82.3 vs. 86.7), adjusted for age and sex (all P < 0.01). A higher percentage of time sedentary and fewer sedentary breaks were associated with a significantly greater likelihood of metabolic syndrome after adjustment for age, sex, ethnicity, education, alcohol consumption, smoking, BMI, diabetes, heart disease, and physical activity. The association between intensity during sedentary time and metabolic syndrome was borderline significant. CONCLUSIONS: The proportion of sedentary time was strongly related to metabolic risk, independent of physical activity. Current results suggest older people may benefit from reducing total sedentary time and avoiding prolonged periods of sedentary time by increasing the number of breaks during sedentary time.
To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM).
In this international, ...multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and
mutation status.
Four hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided
= .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided
< .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided
= .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided
= .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4%
49.3%). Both groups received full chemotherapy dose intensity.
The addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.
Hydride ion from the neutral gold cycloheptatrienyl complex (P)Au(η1‐C7H7) (P=P(tBu)2(o‐biphenyl)) with triphenylcarbenium tetrafluoroborate at −80 °C led to the isolation of the cationic gold ...cycloheptatrienylidene complex (P)Au(η1‐C7H6)+ BF4− in 52 % yield, which was characterized in solution and by single‐crystal X‐ray diffraction. This cycloheptatrienylidene complex represents the first example of a gold carbenoid complex that lacks conjugated heteroatom stabilization of the electron‐deficient C1 carbon atom. The cycloheptatrienylidene ligand of this complex is reactive; it can be reduced by mild hydride donors, and converted to tropone in the presence of pyridine N‐oxide.
Hydride ion from the neutral gold cycloheptatrienyl complex 1 (P=P(tBu)2 (o‐biphenyl)) with Ph3C+ BF4− formed the cationic gold cycloheptatrienylidene complex 2, which was characterized by single‐crystal X‐ray diffraction. The cycloheptatrienylidene ligand of 2 is reactive; it can be reduced by mild hydride donors, and converted into tropone in the presence of pyridine N‐oxide.
NCI-MATCH is a nationwide, histology-agnostic, signal-finding, molecular profile-driven trial for patients with refractory cancers, lymphomas, or myelomas. Patients with tumors harboring actionable ...aberration(s) in fibroblast growth factor receptor (
)
were treated with AZD4547, an oral FGFR1-3 inhibitor.
Patients' tumors were screened by next-generation sequencing for predefined
amplification, activating mutations, or fusions. Patients were treated with AZD4547, 80 mg orally twice daily until progression of disease or drug intolerance. A response rate of 16% was considered promising.
Between July 2016 and June 2017, 70 patients were assigned and 48 received protocol therapy and are eligible for analysis. Patients' tumors harbored
or
amplification (n = 20),
or
single-nucleotide variants (n = 19), or
or
fusions (n = 9). The most common primary tumors were breast (33.3%), urothelial (12.5%), and cervical cancer (10.4%).Grade 3 adverse events were consistent with those described in previous clinical trials. Confirmed partial responses were seen in 8% (90% CI, 3% to 18%) and were observed only in patients whose tumors harbored
point mutations or fusions. Stable disease was observed in 37.5% (90% CI, 25.8% to 50.4%). The median progression-free survival (PFS) was 3.4 months, and the 6-month PFS rate was 15% (90% CI, 8% to 31%). For patients with tumors harboring
fusions, the response rate was 22% (90% CI, 4.1% to 55%), and 6-month PFS rate was 56% (90% CI, 31% to 100%).
Preliminary signals of activity appeared to be limited to cancers harboring
activating mutations and fusions, although AZD4547 did not meet the primary end point. Different
somatic alterations may confer different levels of signaling potency and/or oncogene dependence.
To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare.
The Treatment of Graves' Orbitopathy to Reduce Proptosis ...with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial.
Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC.
OPTIC nonresponders or those who flared (≥2-mm increase in proptosis, ≥2-point increase in clinical activity score CAS, or both) during follow-up were treated for the first time (previous placebo patients) or re-treated with teprotumumab in OPTIC-X with 8 infusions over 24 weeks.
Proptosis response and safety. Secondary outcomes included proptosis, CAS, subjective diplopia, and quality-of-life.
Thirty-three of 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean ± standard deviation, -3.5 ± 1.7 mm) when treated with teprotumumab in OPTIC-X. The responses were equivalent to the OPTIC study. In these responders, proptosis, CAS of 0 or 1, and diplopia responses were maintained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at follow-up week 48. The median TED duration was 12.9 months versus 6.3 months in those treated with teprotumumab in the OPTIC study. Of the 5 OPTIC teprotumumab nonresponders re-treated in OPTIC-X, 2 responded, 1 showed a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatment early. Of the OPTIC teprotumumab responders who experienced flare, 5 of 8 patients (62.5%) responded when re-treated (mean proptosis reduction, 1.9 ± 1.2 mm from OPTIC-X baseline and 3.3 ± 0.7 mm from OPTIC baseline). Compared with published double-masked trials and their integrated follow-up, no new safety signals were identified. Mild hearing impairment was reported; 4 events occurred during the first course of treatment, and 2 events reoccurred after re-treatment.
Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.
Although chondrogenesis and osteogenesis are considered as two separate processes during endochondral bone formation after birth, recent studies have demonstrated the direct cell transformation from ...chondrocytes into bone cells in postnatal bone growth. Here we use cell lineage tracing and multiple in vivo approaches to study the role of Bmpr1a in endochondrogenesis. Our data showed profound changes in skeletal shape, size and structure when Bmpr1a was deleted using Aggrecan-Cre
in early cartilage cells with a one-time tamoxifen injection. We observed the absence of lineage progression of chondrocyte-derived bone cells to form osteoblasts and osteocytes in metaphyses. Furthermore, we demonstrated the key contribution of growth plate chondrocytes and articular chondrocytes, not only for long bone growth, but also for bone remodeling. In contrast, deleting Bmpr1a in early osteoblasts with 3.6 Col 1-Cre had little impact on skeletal shape and size except for a sharp increase in osteoblasts and osteocytes, leading to a profound increase in bone volume. We conclude that chondrogenesis and osteogenesis are one continuous developmental and lineage-defined biological process, in which Bmpr1a signaling in chondrocytes is necessary for the formation of a pool or niche of osteoprogenitors that then contributes in a major way to overall bone formation and growth.
Interstitial tissue acidosis resulting from abnormal perfusion and metabolism is a hallmark of cancer. The current study demonstrates that chemical exchange saturation transfer (CEST) MRI can be used ...as a noninvasive pH-weighted molecular imaging technique by targeting the chemical exchange between amine protons and protons in extracellular bulk water.
First, the sensitivity of amine CEST was validated in phantoms under a variety of conditions, including different magnetic field strengths, amino acid concentrations, and pH values. Amine CEST was compared with histology in both a preclinical GL261 intracranial glioma model at 7T and human patients at 3T. The association between physiologic and pH-weighted MRI was explored, along with the ability to predict time to progression to radiochemotherapy in 20 glioblastoma patients.
z-Spectral asymmetry increased at 3 ppm (amine range) on CEST MRI with decreasing pH within the range observed in tumors for both 3T and 7T scanners. Lesions with acidic signatures showed active tumor and pseudopalisading tumor on histology and showed elevated FDOPA PET uptake, lactate on MR spectroscopy, and perfusion abnormalities. Patients with acidic lesions after surgery or stable/growing acidic lesions had a shorter time to progression following radiochemotherapy compared with patients with lesions demonstrating relatively low acidity (P < .001).
Results suggest pH-weighted MRI may provide new insight into brain tumor physiology beyond traditional imaging technologies.
Objective To test whether community mobilization adds effectiveness to conventional dengue control.Design Pragmatic open label parallel group cluster randomized controlled trial. Those assessing the ...outcomes and analyzing the data were blinded to group assignment. Centralized computerized randomization after the baseline study allocated half the sites to intervention, stratified by country, evidence of recent dengue virus infection in children aged 3-9, and vector indices.Setting Random sample of communities in Managua, capital of Nicaragua, and three coastal regions in Guerrero State in the south of Mexico.Participants Residents in a random sample of census enumeration areas across both countries: 75 intervention and 75 control clusters (about 140 households each) were randomized and analyzed (60 clusters in Nicaragua and 90 in Mexico), including 85 182 residents in 18 838 households.Interventions A community mobilization protocol began with community discussion of baseline results. Each intervention cluster adapted the basic intervention—chemical-free prevention of mosquito reproduction—to its own circumstances. All clusters continued the government run dengue control program.Main outcome measures Primary outcomes per protocol were self reported cases of dengue, serological evidence of recent dengue virus infection, and conventional entomological indices (house index: households with larvae or pupae/households examined; container index: containers with larvae or pupae/containers examined; Breteau index: containers with larvae or pupae/households examined; and pupae per person: pupae found/number of residents). Per protocol secondary analysis examined the effect of Camino Verde in the context of temephos use.Results With cluster as the unit of analysis, serological evidence from intervention sites showed a lower risk of infection with dengue virus in children (relative risk reduction 29.5%, 95% confidence interval 3.8% to 55.3%), fewer reports of dengue illness (24.7%, 1.8% to 51.2%), fewer houses with larvae or pupae among houses visited (house index) (44.1%, 13.6% to 74.7%), fewer containers with larvae or pupae among containers examined (container index) (36.7%, 24.5% to 44.8%), fewer containers with larvae or pupae among houses visited (Breteau index) (35.1%, 16.7% to 55.5%), and fewer pupae per person (51.7%, 36.2% to 76.1%). The numbers needed to treat were 30 (95% confidence interval 20 to 59) for a lower risk of infection in children, 71 (48 to 143) for fewer reports of dengue illness, 17 (14 to 20) for the house index, 37 (35 to 67) for the container index, 10 (6 to 29) for the Breteau index, and 12 (7 to 31) for fewer pupae per person. Secondary per protocol analysis showed no serological evidence of a protective effect of temephos.Conclusions Evidence based community mobilization can add effectiveness to dengue vector control. Each site implementing the intervention in its own way has the advantage of local customization and strong community engagement. Trial registration ISRCTN27581154
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