Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment ...options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multidisciplinary NF1 experts.
Cytotoxic T‐lymphocyte associated protein‐4 (CTLA‐4) and the Programmed Death Receptor 1 (PD‐1) are immune checkpoint molecules that are well‐established targets of antibody immunotherapies for the ...management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune‐related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use.
Combination checkpoint inhibitor therapy with the anti‐PD‐1 Nivolumab and anti‐CTLA‐4 Ipilimumab antibodies is approved in advanced melanoma. This may offer enhanced efficacy over single agent treatments but is associated with toxicity. Herein, we summarize evidence for the potential merits, immunological mechanisms, and clinical challenges of combination treatment compared with monotherapy.
IMPORTANCE: Hypoglycemia is common during neonatal transition and may cause permanent neurological impairment, but optimal intervention thresholds are unknown. OBJECTIVE: To test the hypothesis that ...neurodevelopment at 4.5 years is related to the severity and frequency of neonatal hypoglycemia. DESIGN, SETTING, AND PARTICIPANTS: The Children With Hypoglycemia and Their Later Development (CHYLD) Study is a prospective cohort investigation of moderate to late preterm and term infants born at risk of hypoglycemia. Clinicians were masked to neonatal interstitial glucose concentrations; outcome assessors were masked to neonatal glycemic status. The setting was a regional perinatal center in Hamilton, New Zealand. The study was conducted from December 2006 to November 2010. The dates of the follow-up were September 2011 to June 2015. Participants were 614 neonates born from 32 weeks’ gestation with at least 1 risk factor for hypoglycemia, including diabetic mother, preterm, small, large, or acute illness. Blood and masked interstitial glucose concentrations were measured for up to 7 days after birth. Infants with hypoglycemia (whole-blood glucose concentration <47 mg/dL) were treated to maintain blood glucose concentration of at least 47 mg/dL. EXPOSURES: Neonatal hypoglycemic episode, defined as at least 1 consecutive blood glucose concentration less than 47 mg/dL, a severe episode (<36 mg/dL), or recurrent (≥3 episodes). An interstitial episode was defined as an interstitial glucose concentration less than 47 mg/dL for at least 10 minutes. MAIN OUTCOMES AND MEASURES: Cognitive function, executive function, visual function, and motor function were assessed at 4.5 years. The primary outcome was neurosensory impairment, defined as poor performance in one or more domains. RESULTS: In total, 477 of 604 eligible children (79.0%) were assessed. Their mean (SD) age at the time of assessment was 4.5 (0.1) years, and 228 (47.8%) were female. Those exposed to neonatal hypoglycemia (280 58.7%) did not have increased risk of neurosensory impairment (risk difference RD, 0.01; 95% CI, −0.07 to 0.10 and risk ratio RR, 0.96; 95% CI, 0.77 to 1.21). However, hypoglycemia was associated with increased risk of low executive function (RD, 0.05; 95% CI, 0.01 to 0.10 and RR, 2.32; 95% CI, 1.17 to 4.59) and visual motor function (RD, 0.03; 95% CI, 0.01 to 0.06 and RR, 3.67; 95% CI, 1.15 to 11.69), with highest risk in children exposed to severe, recurrent, or clinically undetected (interstitial episodes only) hypoglycemia. CONCLUSIONS AND RELEVANCE: Neonatal hypoglycemia was not associated with increased risk of combined neurosensory impairment at 4.5 years but was associated with a dose-dependent increased risk of poor executive function and visual motor function, even if not detected clinically, and may thus influence later learning. Randomized trials are needed to determine optimal screening and intervention thresholds based on assessment of neurodevelopment at least to school age.
Annular structures (rings and gaps) in disks around pre-main-sequence stars have been detected in abundance towards class II protostellar objects that are approximately 1,000,000 years old
. These ...structures are often interpreted as evidence of planet formation
, with planetary-mass bodies carving rings and gaps in the disk
. This implies that planet formation may already be underway in even younger disks in the class I phase, when the protostar is still embedded in a larger-scale dense envelope of gas and dust
. Only within the past decade have detailed properties of disks in the earliest star-forming phases been observed
. Here we report 1.3-millimetre dust emission observations with a resolution of five astronomical units that show four annular substructures in the disk of the young (less than 500,000 years old)
protostar IRS 63. IRS 63 is a single class I source located in the nearby Ophiuchus molecular cloud at a distance of 144 parsecs
, and is one of the brightest class I protostars at millimetre wavelengths. IRS 63 also has a relatively large disk compared to other young disks (greater than 50 astronomical units)
. Multiple annular substructures observed towards disks at young ages can act as an early foothold for dust-grain growth, which is a prerequisite of planet formation. Whether or not planets already exist in the disk of IRS 63, it is clear that the planet-formation process begins in the initial protostellar phases, earlier than predicted by current planet-formation theories
.
The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, the largest national precision oncology study to date (> 1,100 sites) of patients with relapsed or refractory ...malignancies, assigned patients to targeted therapy in parallel phase II studies based on tumor molecular alterations. The anti-programmed death receptor 1 inhibitor nivolumab previously showed activity in mismatch repair (MMR)-deficient colon cancer. We hypothesized that nivolumab would have activity in patients with MMR-deficient, noncolorectal tumors.
Eligible patients with relapsed or refractory tumors, good end-organ function, and Eastern Cooperative Oncology Group performance status of ≤ 1 underwent tumor biopsy for centralized screening of molecular alterations. MMR deficiency was defined by complete loss of nuclear expression of
or
MMR gene products by immunohistochemistry (IHC). Patients with MMR-deficient colorectal cancer were excluded. Nivolumab, 3 mg/kg every 2 weeks (28-day cycles) and 480 mg every 4 weeks after cycle 4, was administered intravenously. Disease reassessment was performed every 2 cycles. The primary end point was RECIST 1.1 objective response rate (ORR).
Two percent of 4,902 screened patients had an MMR-deficient cancer by IHC. Forty-two evaluable patients were enrolled, with a median age of 60 years and a median of 3 prior therapies. The most common histologies were endometrioid endometrial adenocarcinoma (n = 13), prostate adenocarcinoma (n = 5), and uterine carcinosarcoma (n = 4). ORR was 36% (15 of 42 patients). An additional 21% of patients had stable disease. The estimated 6-, 12-, and 18-month progression-free survival rates were 51.3% (90% CI, 38.2% to 64.5%), 46.2% (90% CI, 33.1% to 59.3%), and 31.4% (90% CI, 18.7% to 44.2%), respectively. Median overall survival was 17.3 months. Toxicity was predominantly low grade.
A variety of refractory cancers (2.0% of those screened) had MMR deficiency as defined in NCI-MATCH. Nivolumab has promising activity in MMR-deficient noncolorectal cancers of a wide variety of histopathologic types.
To characterize associations between exposures within and outside the medical workplace with healthcare personnel (HCP) SARS-CoV-2 infection, including the effect of various forms of respiratory ...protection.
Case-control study.
We collected data from international participants via an online survey.
In total, 1,130 HCP (244 cases with laboratory-confirmed COVID-19, and 886 controls healthy throughout the pandemic) from 67 countries not meeting prespecified exclusion (ie, healthy but not working, missing workplace exposure data, COVID symptoms without lab confirmation) were included in this study.
Respondents were queried regarding workplace exposures, respiratory protection, and extra-occupational activities. Odds ratios for HCP infection were calculated using multivariable logistic regression and sensitivity analyses controlling for confounders and known biases.
HCP infection was associated with non-aerosol-generating contact with COVID-19 patients (adjusted OR, 1.4; 95% CI, 1.04-1.9; P = .03) and extra-occupational exposures including gatherings of ≥10 people, patronizing restaurants or bars, and public transportation (adjusted OR range, 3.1-16.2). Respirator use during aerosol-generating procedures (AGPs) was associated with lower odds of HCP infection (adjusted OR, 0.4; 95% CI, 0.2-0.8, P = .005), as was exposure to intensive care and dedicated COVID units, negative pressure rooms, and personal protective equipment (PPE) observers (adjusted OR range, 0.4-0.7).
COVID-19 transmission to HCP was associated with medical exposures currently considered lower-risk and multiple extra-occupational exposures, and exposures associated with proper use of appropriate PPE were protective. Closer scrutiny of infection control measures surrounding healthcare activities and medical settings considered lower risk, and continued awareness of the risks of public congregation, may reduce the incidence of HCP infection.
We present the full disk-fit results VANDAM survey of all Class 0 and I protostars in the Perseus molecular cloud. We have 18 new protostellar disk candidates around Class 0 and I sources, which are ...well described by a simple, parametrized disk model fit to the 8 mm VLA dust continuum observations. 33% of Class 0 protostars and just 11% of Class I protostars have candidate disks, while 78% of Class 0 and I protostars do not have signs of disks within our 12 au disk diameter resolution limit, indicating that at 8 mm most disks in the Class 0 and I phases are <10 au in radius. These small radii may be a result of surface brightness sensitivity limits. Modeled 8 mm radii are similar to the radii of known Class 0 disks with detected Keplerian rotation. Since our 8 mm data trace a population of larger dust grains that radially drift toward the protostar and are lower limits on true disk sizes, large disks at early times do not seem to be particularly rare. We find statistical evidence that Class 0 and I disks are likely drawn from the same distribution, meaning disk properties may be defined early in the Class 0 phase and do not undergo large changes through the Class I phase. By combining our candidate disk properties with previous polarization observations, we find a qualitative indication that misalignment between inferred envelope-scale magnetic fields and outflows may indicate disks on smaller scales in Class 0 sources.
We present a high angular resolution millimeter-wave dust continuum imaging survey of circumstellar material associated with the individual components of 23 multiple star systems in the Taurus-Auriga ...young cluster. Approximately one-third (28%-37%) of the individual stars in multiple systems have detectable millimeter emission, an incidence rate half that for single stars (~62%) which does not depend on the number of companions. There is a strong, positive correlation between the luminosity and projected separation (a sub(p)) of a stellar pair. Wide pairs (a sub(p) > 300 AU) have a similar luminosity distribution as single stars, medium pairs (a sub(p) approximately 30-300 AU) are a factor of five fainter, and close pairs (a sub(p) < 30 AU) are ~5x fainter yet (aside from a small, but notable population of bright circumbinary disks). A direct comparison of resolved disk sizes with predictions from tidal truncation models yields mixed results; some disks are much larger than expected given the projected distances of their companions.
Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or ...silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses.
Optical fibers have altered astronomical instrument design by allowing for a complex, often large instrument to be mounted in a remote and stable location with respect to the telescope. The fibers ...also enable the possibility to rearrange the signal from a focal plane to form a psuedo-slit at the entrance to a spectrograph, optimizing the detector usage and enabling the study of hundreds of thousands of stars or galaxies simultaneously. Multi-core fibers in particular offer several favorable properties with respect to traditional fibers: 1) the separation between single-mode cores is greatly reduced and highly regular with respect to free standing fibers, 2) they offer a monolithic package with multi-fiber capabilities and 3) they operate at the diffraction limit. These properties have enabled the realization of single component photonic lanterns, highly simplified fiber Bragg gratings, and advanced fiber mode scramblers. In addition, the precise grid of cores has enabled the design of efficient single-mode fiber integral field units for spectroscopy. In this article, we provide an overview of the broad range of applications enabled by multi-core fiber technology in astronomy and outline future areas of development.
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