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Probabilistic machine learning utilizes controllable sources of randomness to encode uncertainty and enable statistical modeling. Harnessing the pure randomness of quantum vacuum noise, which stems from fluctuating electromagnetic fields, has shown promise for high speed and energy-efficient stochastic photonic elements. Nevertheless, photonic computing hardware which can control these stochastic elements to program probabilistic machine learning algorithms has been limited. Here, we implement a photonic probabilistic computer consisting of a controllable stochastic photonic element - a photonic probabilistic neuron (PPN). Our PPN is implemented in a bistable optical parametric oscillator (OPO) with vacuum-level injected bias fields. We then program a measurement-and-feedback loop for time-multiplexed PPNs with electronic processors (FPGA or GPU) to solve certain probabilistic machine learning tasks. We showcase probabilistic inference and image generation of MNIST-handwritten digits, which are representative examples of discriminative and generative models. In both implementations, quantum vacuum noise is used as a random seed to encode classification uncertainty or probabilistic generation of samples. In addition, we propose a path towards an all-optical probabilistic computing platform, with an estimated sampling rate of  ~1 Gbps and energy consumption of  ~5 fJ/MAC. Our work paves the way for scalable, ultrafast, and energy-efficient probabilistic machine learning hardware., (© 2024. The Author(s).)

Importance: Absolute neutrophil counts (ANCs) are used to determine cancer clinical trial (CCT) eligibility and systemic anticancer therapy (SACT) dose modifications. Duffy null-associated ANC (DANC) is a nonpathologic phenotype associated with lower ANC and most frequently seen in individuals with African and Middle Eastern ancestry. It is unclear whether CCTs exclude or SACT regimens modify doses for individuals with ANC within the DANC reference range., Objective: To investigate CCT exclusions and SACT dose modifications for ANC within the DANC reference range., Design, Setting, and Participants: This cross-sectional study of contemporary CCTs and SACT regimens included adult, interventional, phase 3 CCTs for the 5 most prevalent cancers in the US and United Kingdom (prostate, breast, melanoma, colorectal, and lung cancers) testing SACTs with start dates between November 1, 2021, and November 1, 2023, and that were registered on ClinicalTrials.gov. Preferred curative-intent SACT regimens were listed in National Comprehensive Cancer Network guidelines., Exposure: Cancer clinical trial exclusions and SACT regimen modifications., Main Outcome and Measures: Proportions of CCTs that exclude and SACT regimens that modify doses for individuals with an ANC within the DANC reference range., Results: For CCTs, 289 of 382 trials (75.7%) were eligible, of which 221 (76.5% [95% CI, 71.1%-81.2%]) excluded patients with ANC values within the DANC reference range. Colorectal CCTs had the highest (38 of 44 [86.4% (95% CI, 72.6%-94.8%)]) and prostate CCTs had the lowest (11 of 23 [47.8% (95% CI, 26.8%-69.4%)]) proportions of exclusions. Of CCTs testing cytotoxic chemotherapy, 116 of 142 (81.7% [95% CI, 74.3%-87.7%]) had exclusions; 93 of 123 (75.6% [95% CI, 67.0%-82.9%]) CCTs testing targeted therapies alone and 12 of 24 (50.0% [95% CI, 29.1%-70.9%]) testing hormonal therapies alone had exclusions. Among the 113 US- and UK-based trials, exclusions were present in 89 (78.8% [95% CI, 70.1%-85.9%]). Of 71 SACT regimens, 38 (53.5% [95% CI, 41.3%-65.5%]) included dose modifications for ANC values within the DANC reference range. Lung cancer regimens had the highest (23 of 31 [74.2% (95% CI, 55.4%-88.1%)]) and prostate cancer had the lowest (0 of 12 [0 (95% CI, 0%-26.4%)]) proportions of modifications. Regimens including chemotherapy had modifications in 32 of 44 (72.7% [95% CI, 57.2%-85.0%]); 11 of 20 (55.0% [95% CI, 31.5%-76.9%]) of targeted therapy regimens and 0 of 16 (0% [95% CI, 0%-20.6%]) of hormonal therapy regimens had modifications. Among regimens including chemotherapy and/or targeted therapy, modifications were present in 38 of 55 (69.1% [95% CI, 49.7%-73.2%])., Conclusions and Relevance: In this cross-sectional study, substantial proportions of CCTs excluded and SACT regimens modified doses for patients with ANCs in the DANC reference range. These practices structurally discriminate against patients of African and Middle Eastern ancestry. While determining optimal SACT dose modifications requires further study, CCT exclusion criteria should be revised.

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and the rising availability of neuroimaging. While most exhibit non-malignant behaviour, a subset of meningiomas are biologically aggressive and lead to significant neurological morbidity and mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) working group. There also remains clinical equipoise on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas (ICOM) including field-leading experts, have prepared a comprehensive consensus narrative review directed towards clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality of life studies, and management strategies for unique meningioma patient populations. In each section we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study (n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1- 13 C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Multiplexed analysis in medical diagnostics is widely accepted as a more thorough and complete method compared to single-analyte detection. While analytical methods like polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) exist for multiplexed detection of biomarkers, they remain time-consuming and expensive. Lateral flow assays (LFAs) are an attractive option for point-of-care testing, and examples of multiplexed LFAs exist. However, these devices are limited by spatial resolution of test lines, large sample volume requirements, cross-reactivity, and poor sensitivity. Recent work has developed capillary-flow microfluidic ELISA platforms as a more sensitive alternative to LFAs; however, multiplexed detection on these types of devices has yet to be demonstrated. In the aftermath of the initial SARS-CoV-2 pandemic, the need for rapid, sensitive point-of-care devices has become ever clearer. Moving forward, devices that can distinguish between diseases with similar presenting symptoms would be the ideal home diagnostic. Here, the first example of a multiplexed capillary-flow immunoassay device for the simultaneous detection of multiple biomarkers is reported. From a single sample addition step, the reagents and washing steps required for two simultaneous ELISAs are delivered to spatially separated test strips. Visual results can be obtained in <15 min, and images captured with a smartphone can be analyzed for quantitative data. This device was used to distinguish between and quantify H1N1 hemagglutinin (HA) and SARS-CoV-2 nucleocapsid protein (N-protein). Using this device, analytical detection limits of 840 and 133 pg/mL were obtained for hemagglutinin and nucleocapsid protein, respectively. The presence of one target in the device did not increase the signal on the other test line, indicating no cross-reactivity between the assays. Additionally, simultaneous detection of both N-protein and HA was performed as well as simultaneous detection of N-protein and human C-reactive protein (CRP). Elevated levels of CRP in a patient infected with SARS-CoV-2 have been shown to correlate with more severe outcomes and a greater risk of death as well. To further expand on the simultaneous detection of two biomarkers, CRP and N-protein were detected simultaneously, and the presence of SARS-CoV-2 N-protein did not interfere with the detection of CRP when both targets were present in the sample.

Plant reproduction is a complex, highly-coordinated process in which a single, male germ cell grows through the maternal reproductive tissues to reach and fertilise the egg cell. Focussing on Arabidopsis thaliana, we review signalling between male and female partners which is important throughout the pollen tube journey, especially during pollen tube reception at the ovule. Numerous receptor kinases and their coreceptors are implicated in signal perception in both the pollen tube and synergid cells at the ovule entrance, and several specific peptide and carbohydrate ligands for these receptors have recently been identified. Clarifying the interplay between these signals and the downstream responses they instigate presents a challenge for future research and may help to illuminate broader principles of plant cell-cell communication., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder characterized by a collection of clinical features including mild to severe intellectual disability, hypertonia, marfanoid habitus, facial asymmetry, osteoporosis, developmental delay and seizures. Whole genome sequencing (WGS) identified a mutation in the spermine synthase ( SMS ) gene (c.746 A>G, p.Tyr249Cys) in a male with kyphosis, seizures, and osteoporosis. His phenotype is unique in that he does not have intellectual disability (ID) but does have a mild learning disability. This case demonstrates a milder presentation of SRS and expands the phenotype beyond the reported literature.

The mesophyll cells of grass leaves, such as rice, are traditionally viewed as displaying a relatively uniform pattern, in contrast to the clear distinctions of palisade and spongy layers in typical eudicot leaves. This quantitative analysis of mesophyll cell size and shape in rice leaves reveals that there is an inherent pattern in which cells in the middle layer of the mesophyll are larger and less circular and have a distinct orientation of their long axis compared to mesophyll cells in other layers. Moreover, this pattern was observed in a range of rice cultivars and species. The significance of this pattern with relation to potential photosynthetic function and the implication of the widespread use of middle layer mesophyll cells as typical of the rice leaf have been investigated and discussed., Competing Interests: No conflict of interest declared., (© 2023 The Authors. Plant Direct published by American Society of Plant Biologists and the Society for Experimental Biology and John Wiley & Sons Ltd.)

Temperature cycling stability studies can be appropriately designed and utilized to ensure that drug product quality, efficacy, and safety are not compromised when materials are subjected to short term temperature excursions from intended storage that may occur during e.g., shipping, transport, or patient use. Some countries, such as Australia and Brazil, impose specific regulations that specify the need to conduct stability studies that are supportive of "real world" excursions as part of licensing approval requirements. These temperature cycling stability studies extend beyond what is described in ICH Guidelines Q1A(R2) and Q5C, and companies may be challenged in designing studies that not only satisfy country specific regulations, but also satisfy all global regulatory health authority expectations. This article focuses on responses to a cross-industry survey conducted within the International Consortium for Innovation and Quality (iqconsortium.org) member companies, regarding practices related to temperature cycling stability studies, in order to determine how these requirements are being interpreted and met. The results indicate that while there is no one-size-fits-all approach to performing temperature cycling stability studies, there are common and best practices that can be followed to satisfy global health authority regulatory guidelines and requirements. PURPOSE: The purpose of this paper is to describe the outcome of an industry survey and common/best practices on temperature cycling stability studies performed on drug product (DP) to satisfy the requirements established for marketing authorizations in Australia and Brazil or any other countries that may have similar requirements. The framework is proposed within the context of late phase and commercial development of common biological and/or large molecule modalities, such as monoclonal antibodies (mAbs, including bispecific antibodies), fusion proteins, complex proteins, oligonucleotides, and antibody-drug conjugates (ADCs), but many of the general principles involved may be applied to other therapeutics, such as Virus Like Particles (VLP), gene or cell therapies (GTx or CTx), or vaccines. For the purposes of this paper, temperature cycling stability studies refer to studies that are designed, in part, to support short term temperature excursions that drug product may be subjected to during shipping and storage activities and is outside of the labeled storage condition of the product., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Nonclassical states of light, such as number-squeezed light, with fluctuations below the classical shot noise level, have important uses in metrology, communication, quantum information processing, and quantum simulation. However, generating these nonclassical states of light, especially with high intensity and a high degree of squeezing, is challenging. To address this problem, we introduce a new concept which uses gain to generate intense sub-Poissonian light at optical frequencies. It exploits a strongly nonlinear gain for photons which arises from a combination of frequency-dependent gain and Kerr nonlinearity. In this laser architecture, the interaction between the gain medium and Kerr nonlinearity suppresses the spontaneous emission at high photon number states, leading to a strong "negative feedback" that suppresses photon-number fluctuations. We discuss realistic implementations of this concept based on the use of solid-state gain media in laser cavities with Kerr nonlinear materials, showing how 90% squeezing of photon number fluctuations below the shot noise level can be realized.

Background: Malignant small bowel obstruction has a poor prognosis and is associated with multiple related symptoms. The optimal treatment approach is often unclear. We aimed to compare surgical versus non-surgical management with the aim to determine the optimal approach for managing malignant bowel obstruction., Methods: S1316 was a pragmatic comparative effectiveness trial done within the National Cancer Trials Network at 30 hospital and cancer research centres in the USA, Mexico, Peru, and Colombia. Participants had an intra-abdominal or retroperitoneal primary cancer confirmed via pathological report and malignant bowel disease; were aged 18 years or older with a Zubrod performance status 0-2 within 1 week before admission; had a surgical indication; and treatment equipoise. Participants were randomly assigned (1:1) to surgical or non-surgical treatment using a dynamic balancing algorithm, balancing on primary tumour type. Patients who declined consent for random assignment were offered a prospective observational patient choice pathway. The primary outcome was the number of days alive and out of the hospital (good days) at 91 days. Analyses were based on intention-to-treat linear, logistic, and Cox regression models combining data from both pathways and adjusting for potential confounders. Treatment complications were assessed in all analysed patients in the study. This completed study is registered with ClinicalTrials.gov, NCT02270450., Findings: From May 11, 2015, to April 27, 2020, 221 patients were enrolled (143 [65%] were female and 78 [35%] were male). There were 199 evaluable participants: 49 in the randomised pathway (24 surgery and 25 non-surgery) and 150 in the patient choice pathway (58 surgery and 92 non-surgery). No difference was seen between surgery and non-surgery for the primary outcome of good days: mean 42·6 days (SD 32·2) in the randomised surgery group, 43·9 days (29·5) in the randomised non-surgery group, 54·8 days (27·0) in the patient choice surgery group, and 52·7 days (30·7) in the patient choice non-surgery group (adjusted mean difference 2·9 additional good days in surgical versus non-surgical treatment [95% CI -5·5 to 11·3]; p=0·50). During their initial hospital stay, six participants died, five due to cancer progression (four patients from the randomised pathway, two in each treatment group, and one from the patient choice pathway, in the surgery group) and one due to malignant bowel obstruction treatment complications (patient choice pathway, non-surgery). The most common grade 3-4 malignant bowel obstruction treatment complication was anaemia (three [6%] patients in the randomised pathway, all in the surgical group, and five [3%] patients in the patient choice pathway, four in the surgical group and one in the non-surgical group)., Interpretation: In our study, whether patients received a surgical or non-surgical treatment approach did not influence good days during the first 91 days after registration. These findings should inform treatment decisions for patients hospitalised with malignant bowel obstruction., Funding: Agency for Healthcare Research and Quality and the National Cancer Institute., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests GLA received payments to Fred Hutch for support for the present manuscript. AAS has grants or contracts from AbbVie, Aravive, AstraZeneca, Boehringer, Ingelheim, Clovis, Eisai, Ellipses, Immunogen, Merck, Oncoquest, Roche/Genentech, SeagenInc, TapImmune, Tesaro/GSK, VBL Therapeutics, and National Cancer Trial Network; has received honoraria for educational presentations or lectures from @Point of Care, Clinical Care Optios, Curio Science, Peerview, Bio ASCEND, RTP, and GOG Foundation; has received honorarium from Myriad; and has received support for attending meetings or travel from GOG, Society of Gynecologic Oncology, and NRG. DCF received support for the present manuscript in the form of payments through S1316 to Valley Health for patient enrolment; received payment or honoraria for lectures from Intuitive for the resident lecture programme; and has stock options in Intuitive. JDW has grants or contracts from Merck; receives royalties or licenses from UptoDate; receives payments for expert testimony from Medicolegal for consulting on gynaecological cancer; is a journal editor for the American College of Obstetricians and Gynecologists. BFa received visiting professor honoraria in April, 2022, at the Ohio State University Department of Surgery, October, 2021, at the University of Nebraska Department of Surgery, and December, 2020, at the University of Tennessee Department of Surgery; and has stock or stock options in Align Tech, Biogen, Bristol Myers Squibb, DexCom, Editas Medicine, Fulgent Genetics, GoodRx Holdings, Guardant Health, Globus Medical, Healthequity, HCA Healthcare, IDEXX Laboratories, Illumina, Intuitive Surgical, Invitae, Masimo, Moderna, Neurocrine Bioscience, Novocure, Quidel, Repligen, Seagen, Shockwave Medical, STAAR Surgical, UnitedHealth Group, Veeva Systems, Teladoc Health, and ResMed. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: None declared

In August 2022, the Cancer Informatics for Cancer Centers brought together cancer informatics leaders for its biannual symposium, Precision Medicine Applications in Radiation Oncology, co-chaired by Quynh-Thu Le, MD (Stanford University), and Walter J. Curran, MD (GenesisCare). Over the course of 3 days, presenters discussed a range of topics relevant to radiation oncology and the cancer informatics community more broadly, including biomarker development, decision support algorithms, novel imaging tools, theranostics, and artificial intelligence (AI) for the radiotherapy workflow. Since the symposium, there has been an impressive shift in the promise and potential for integration of AI in clinical care, accelerated in large part by major advances in generative AI. AI is now poised more than ever to revolutionize cancer care. Radiation oncology is a field that uses and generates a large amount of digital data and is therefore likely to be one of the first fields to be transformed by AI. As experts in the collection, management, and analysis of these data, the informatics community will take a leading role in ensuring that radiation oncology is prepared to take full advantage of these technological advances. In this report, we provide highlights from the symposium, which took place in Santa Barbara, California, from August 29 to 31, 2022. We discuss lessons learned from the symposium for data acquisition, management, representation, and sharing, and put these themes into context to prepare radiation oncology for the successful and safe integration of AI and informatics technologies.

Quantum field theory suggests that electromagnetic fields naturally fluctuate, and these fluctuations can be harnessed as a source of perfect randomness. Many potential applications of randomness rely on controllable probability distributions. We show that vacuum-level bias fields injected into multistable optical systems enable a controllable source of quantum randomness, and we demonstrated this concept in an optical parametric oscillator (OPO). By injecting bias pulses with less than one photon on average, we controlled the probabilities of the two possible OPO output states. The potential of our approach for sensing sub-photon-level fields was demonstrated by reconstructing the temporal shape of fields below the single-photon level. Our results provide a platform to study quantum dynamics in nonlinear driven-dissipative systems and point toward applications in probabilistic computing and weak field sensing.

Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2A high ) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2A high meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications., (© 2023. The Author(s).)

Background: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci., Methods: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci., Results: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci., Conclusions: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Ma̅nuka honey is known for its strong bioactivity, which arises from the autocatalytic conversion of 1,3-dihydroxyacetone (dihydroxyacetone, DHA) in the floral nectar of Leptospermum scoparium (Myrtaceae) to the non-peroxide antibacterial compound methylglyoxal during honey maturation. DHA is also a minor constituent of the nectar of several other Leptospermum species. This study used high-performance liquid chromatography to test whether DHA was present in the floral nectar of five species in other genera of the family Myrtaceae: Ericomyrtus serpyllifolia (Turcz.) Rye, Chamelaucium sp. Bendering (T.J. Alford 110), Kunzea pulchella (Lindl.) A.S. George, Verticordia chrysantha Endl., and Verticordia picta Endl. DHA was found in the floral nectar of two of the five species: E. serpyllifolia and V. chrysantha . The average amount of DHA detected was 0.08 and 0.64 μg per flower, respectively. These findings suggest that the accumulation of DHA in floral nectar is a shared trait among several genera within the family Myrtaceae. Consequently, non-peroxide-based bioactive honey may be sourced from floral nectar outside the genus Leptospermum .

Objective: Severe maternal morbidity (SMM) is a better indicator of quality of care than maternal mortality, which is a rare event. Risk factors such as advanced maternal age, caesarean section (CS) and obesity are increasing. The aim of this study was to examine the rate and trends in SMM at our hospital over a 20-year period., Study Design: Retrospective review was performed of cases of SMM from January 1st 2000 to December 31st 2019. Yearly rates for SMM and Major Obstetric Haemorrhage (MOH) were calculated (per 1000 maternities) and linear regression analysis was used to model the trends over time. Average SMM and MOH rates were also calculated for the periods 2000-2009 and 2010-2019 and compared using a chi-square test. The patient demographics of the SMM group were compared to the background population delivered at our hospital using a chi-square test., Results: 702 women with SMM were identified out of 162,462 maternities over the study period yielding an incidence of 4.3 per 1000 maternities. When the two time periods (2000-2009 and 2010-2019) are compared, the rate of SMM increased 2.4 vs 6.2 (p < 0.001), largely due to an increase in MOH 1.72 vs 3.86 (p < 0.001) and pulmonary embolus (PE) also increased 0.2 vs 0.5 (p = 0.012). Intensive-care unit (ICU) transfer rates more than doubled 0.19 vs 0.44 (p = 0.006). Eclampsia rates decreased 0.3 vs 0.1 (p = 0.047) but the rate of peripartum hysterectomy 0.39 vs 0.38 (p = 0.495), uterine rupture 0.16 vs 0.14 (p = 0.867), cardiac arrest (0.04 vs 0.04) and cerebrovascular accidents (CVA) (0.04 vs 0.04) remained unchanged. Maternal age > 40 years 9.7% vs 5% (p = 0.005), previous CS 25.7% vs 14.4%; p < 0.001 and multiple pregnancy 8 vs 3.6% (p = 0.002) were more prevalent in the SMM cohort compared to the hospital population., Conclusions: Overall, rates of SMM have increased threefold and transfer for ICU care has doubled over 20 years in our unit. The main driver is MOH. The rate of eclampsia has decreased and peripartum hysterectomy, uterine rupture, CVA and cardiac arrest remain unchanged. Advanced maternal age, previous caesarean delivery and multiple pregnancy were more prevalent in the SMM cohort compared to the background population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Few studies have examined epigenetic age acceleration (AA), the difference between DNA methylation (DNAm) predicted age and chronological age, in relation to somatic genomic features in paired cancer and normal tissue, with less work done in non-European populations. In this study, we aimed to examine DNAm age and its associations with breast cancer risk factors, subtypes, somatic genomic profiles including mutation and copy number alterations and other aging markers in breast tissue of Chinese breast cancer (BC) patients from Hong Kong., Methods: We performed genome-wide DNA methylation profiling of 196 tumor and 188 paired adjacent normal tissue collected from Chinese BC patients in Hong Kong (HKBC) using Illumina MethylationEPIC array. The DNAm age was calculated using Horvath's pan-tissue clock model. Somatic genomic features were based on data from RNA sequencing (RNASeq), whole-exome sequencing (WES), and whole-genome sequencing (WGS). Pearson's correlation (r), Kruskal-Wallis test, and regression models were used to estimate associations of DNAm AA with somatic features and breast cancer risk factors., Results: DNAm age showed a stronger correlation with chronological age in normal (Pearson r = 0.78, P < 2.2e-16) than in tumor tissue (Pearson r = 0.31, P = 7.8e-06). Although overall DNAm age or AA did not vary significantly by tissue within the same individual, luminal A tumors exhibited increased DNAm AA (P = 0.004) while HER2-enriched/basal-like tumors exhibited markedly lower DNAm AA (P = < .0001) compared with paired normal tissue. Consistent with the subtype association, tumor DNAm AA was positively correlated with ESR1 (Pearson r = 0.39, P = 6.3e-06) and PGR (Pearson r = 0.36, P = 2.4e-05) gene expression. In line with this, we found that increasing DNAm AA was associated with higher body mass index (P = 0.039) and earlier age at menarche (P = 0.035), factors that are related to cumulative exposure to estrogen. In contrast, variables indicating extensive genomic instability, such as TP53 somatic mutations, high tumor mutation/copy number alteration burden, and homologous repair deficiency were associated with lower DNAm AA., Conclusions: Our findings provide additional insights into the complexity of breast tissue aging that is associated with the interaction of hormonal, genomic, and epigenetic mechanisms in an East Asian population., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Halide perovskite structures are revolutionizing the design of optoelectronic materials, including solar cells, light-emitting diodes, and photovoltaics when formed at the quantum scale. Four isolated sub-nanometer, or picoscale, halide perovskite structures formed inside ≈1.2-1.6 nm single-walled carbon nanotubes (SWCNTs) by melt insertion from CsPbBr 3 and lead-free CsSnI 3 are reported. Three directly relate to the ABX 3 perovskite archetype while a fourth is a perovskite-like lamellar structure with alternating Cs 4 and polyhedral Sn 4 I x layers. In ≈1.4 nm-diameter SWCNTs, CsPbBr 3 forms Cs 3 Pb II Br 5 nanowires, one ABX 3 unit cell in cross section with the Pb 2+ oxidation state maintained by ordered Cs + vacancies. Within ≈1.2 nm-diameter SWCNTs, CsPbBr 3 and CsSnI 3 form inorganic-polymer-like bilayer structures, one-fourth of an ABX 3 unit cell in cross section with systematically reproduced ABX 3 stoichiometry. Producing these smallest halide perovskite structures at their absolute synthetic cross-sectional limit enables quantum confinement effects with first-principles calculations demonstrating bandgap widening compared to corresponding bulk structural forms., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

A warming climate coupled with reductions in water availability and rising salinity are increasingly affecting rice (Oryza sativa) yields. Elevated temperatures combined with vapour pressure deficit (VPD) rises are causing stomatal closure, further reducing plant productivity and cooling. It is unclear what stomatal size (SS) and stomatal density (SD) will best suit all these environmental extremes. To understand how stomatal differences contribute to rice abiotic stress resilience, we screened the stomatal characteristics of 72 traditionally bred varieties. We found significant variation in SS, SD and calculated anatomical maximal stomatal conductance (g smax ) but did not identify any varieties with SD and g smax as low as transgenic OsEPF1oe plants. Traditionally bred varieties with high SD and small SS (resulting in higher g smax ) typically had lower biomasses, and these plants were more resilient to drought than low SD and large SS plants, which were physically larger. None of the varieties assessed were as resilient to drought or salinity as low SD OsEPF1oe transgenic plants. High SD and small SS rice displayed faster stomatal closure during increasing temperature and VPD, but photosynthesis and plant cooling were reduced. Compromises will be required when choosing rice SS and SD to tackle multiple future environmental stresses., (© 2023 The Authors. New Phytologist © 2023 New Phytologist Foundation.)

The quantization of the electromagnetic field leads directly to the existence of quantum mechanical states, called Fock states, with an exact integer number of photons. Despite these fundamental states being long-understood, and despite their many potential applications, generating them is largely an open problem. For example, at optical frequencies, it is challenging to deterministically generate Fock states of order two and beyond. Here, we predict the existence of an effect in nonlinear optics, which enables the deterministic generation of large Fock states at arbitrary frequencies. The effect, which we call an n -photon bound state in the continuum, is one in which a photonic resonance (such as a cavity mode) becomes lossless when a precise number of photons n is inside the resonance. Based on analytical theory and numerical simulations, we show that these bound states enable a remarkable phenomenon in which a coherent state of light, when injected into a system supporting this bound state, can spontaneously evolve into a Fock state of a controllable photon number. This effect is also directly applicable for creating (highly) squeezed states of light, whose photon number fluctuations are (far) below the value expected from classical physics (i.e., shot noise). We suggest several examples of systems to experimentally realize the effects predicted here in nonlinear nanophotonic systems, showing examples of generating both optical Fock states with large n ( n  >  10), as well as more macroscopic photonic states with very large squeezing, with over 90% less noise (10 dB) than the classical value associated with shot noise.

Studying the optical performance of carbon nanotubes (CNTs) filled with guest materials can reveal the fundamental photochemical nature of ultrathin one-dimensional (1D) nanosystems, which are attractive for applications including photocatalysis. Here, we report comprehensive spectroscopic studies of how infiltrated HgTe nanowires (NWs) alter the optical properties of small-diameter ( d t < 1 nm) single-walled carbon nanotubes (SWCNTs) in different environments: isolated in solution, suspended in a gelatin matrix, and heavily bundled in network-like thin films. Temperature-dependent Raman and photoluminescence measurements revealed that the HgTe NW filling can alter the stiffness of SWCNTs and therefore modify their vibrational and optical modes. Results from optical absorption and X-ray photoelectron spectroscopy demonstrated that the semiconducting HgTe NWs did not provide substantial charge transfer to or from the SWCNTs. Transient absorption spectroscopy further highlighted that the filling-induced nanotube distortion can alter the temporal evolution of excitons and their transient spectra. In contrast to previous studies on functionalized CNTs, where electronic or chemical doping often drove changes to the optical spectra, we highlight structural distortion as playing an important role., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Leaf structure plays an important role in photosynthesis. However, the causal relationship and the quantitative importance of any single structural parameter to the overall photosynthetic performance of a leaf remains open to debate. In this paper, we report on a mechanistic model, eLeaf, which successfully captures rice leaf photosynthetic performance under varying environmental conditions of light and CO 2 . We developed a 3D reaction-diffusion model for leaf photosynthesis parameterised using a range of imaging data and biochemical measurements from plants grown under ambient and elevated CO 2 and then interrogated the model to quantify the importance of these elements. The model successfully captured leaf-level photosynthetic performance in rice. Photosynthetic metabolism underpinned the majority of the increased carbon assimilation rate observed under elevated CO 2 levels, with a range of structural elements making positive and negative contributions. Mesophyll porosity could be varied without any major outcome on photosynthetic performance, providing a theoretical underpinning for experimental data. eLeaf allows quantitative analysis of the influence of morphological and biochemical properties on leaf photosynthesis. The analysis highlights a degree of leaf structural plasticity with respect to photosynthesis of significance in the context of attempts to improve crop photosynthesis., (© 2022 The Authors New Phytologist © 2022 New Phytologist Foundation.)

Purpose: Glioblastoma (GBM) is the most common and deadliest brain tumor with unrelenting and rapid disease progression. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Treatment failure and resistance is the rule and despite advances in imaging technology, early detection of treatment failure or impending resistance remains a challenge. There is a dire, unmet, need in clinical practice for minimally-invasive diagnostic tools to enable timely understanding of disease progression and treatment response. Here, we aim to address this clinical need by leveraging a unique characteristic of GBM: the overexpression of the α2 variant of the IL-13 receptor in over 75% of GBM tumors., Methods: In this study we examined patients with primary GBM from Penn State and Cleveland Clinic compared to healthy controls., Results: IL13Rα2 was detectable in plasma of GBM patients using ELISA but detection could be optimized by PEG precipitation to enrich for extracellular vesicles (EVs). Patients with GBM had elevated levels of plasma IL13Rα2, which correlated to levels of this receptor in the tumor tissue. Elevated plasma levels of IL13Rα2 predicted longer overall survival (OS) (19.8 vs. 13.2 months). Similarly, detection of IL13Rα2 + cells in tumor tissue also predicted longer OS (22.1 vs. 12.2 months)., Conclusion: These findings strongly suggest that expression of the IL13Rα2 receptor confer survival advantage in GBM patients, which can be determined through a minimally-invasive liquid biopsy. Detection of plasma IL13Rα2 can also be used to select GBM patients for targeted tumor therapy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The interaction between platelets and cancer cells has been underexplored in solid tumor models that do not metastasize, for example, glioblastoma (GBM) where metastasis is rare. Histologically, it is known that glioma stem cells (GSCs) are found in perivascular and pseudsopalisading regions of GBM, which are also areas of platelet localization. High platelet counts have been associated with poor clinical outcomes in many cancers. While platelets are known to promote the progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Here, we aimed to understand how the bidirectional interaction between platelets and GSCs drives GBM oncogenesis., Methods: Male and female NSG mice were transplanted with GSC lines and treated with antiplatelet and anti-thrombin inhibitors. Immunofluorescence, qPCR, and Western blots were used to determine expression of coagulation mechanism in GBM tissue and subsequent GSC lines., Results: We show that GSCs activate platelets by endogenous production of all the factors of the intrinsic and extrinsic coagulation cascades in a plasma-independent manner. Therefore, GSCs produce thrombin resulting in platelet activation. We further demonstrate that the endogenous coagulation cascades of these cancer stem cells are tumorigenic: they activate platelets to promote stemness and proliferation in vitro and pharmacological inhibition delays tumor growth in vivo ., Conclusions: Our findings uncover a specific preferential relationship between platelets and GSCs that drive GBM malignancies and identify a therapeutically targetable novel interaction., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) induces deep hematologic responses (HR) in patients with newly diagnosed systemic immunoglobulin light-chain (AL) amyloidosis. Modifying melphalan conditioning dose (mHDM <140 mg/m 2 ) is considered in older patients because of concerns regarding tolerability. Age does not predict frailty, and dose modification could compromise responses in an era where effective non-transplant regimens are available. We analyzed 43 patients ≥ 65 years with AL amyloidosis who underwent SCT at Boston University Amyloidosis Center between 2011 and 2020. Median age was 66 years (range 65-68) versus 69 years (range 65-76) in the HDM and mHDM groups, respectively. HR of ≥ very good partial response at 12 months was 66.7% versus 42.3% for patients treated with HDM versus mHDM. Median progression-free survival (PFS) from day 0 of SCT was not reached versus 12.0 months (P =.13); grade ≥ 3 non-hematologic transplant-related toxicities occurred in 87.5% versus 76.9%; and transplant-related mortality was 0% versus 2.3% in the HDM versus mHDM group, respectively. In carefully selected older patients with AL amyloidosis, HDM is well tolerated. Use of mHDM results in reduced HR and PFS; an important consideration with the advent of highly effective non-transplant therapies., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I > 0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p < .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis., (© 2022 Wiley Periodicals LLC.)

Background: The NIH Revitalization Act, implemented 29 years ago, set to improve the representation of women and minorities in clinical trials. In this study, we investigate progress made in all phase therapeutic clinical trials for neuroepithelial CNS tumors stratified by demographic-specific age-adjusted disease incidence and mortality. Additionally, we identify workforce characteristics associated with clinical trials meeting established accrual benchmarks., Methods: Registry study of published clinical trials for World Health Organization defined neuroepithelial CNS tumors between January 2000 and December 2019. Study participants were obtained from PubMed and ClinicalTrials.gov. Population-based data originated from the CBTRUS for incidence analyses. SEER-18 Incidence-Based Mortality data was used for mortality analysis. Descriptive statistics, Fisher exact, and χ 2 tests were used for data analysis., Results: Among 662 published clinical trials representing 49 907 participants, 62.5% of participants were men and 37.5% women (P < .0001) representing a mortality specific over-accrual for men (P = .001). Whites, Asians, Blacks, and Hispanics represented 91.7%, 1.5%, 2.6%, and 1.7% of trial participants. Compared with mortality, Blacks (47% of expected mortality, P = .008), Hispanics (17% of expected mortality, P < .001) and Asians (33% of expected mortality, P < .001) were underrepresented compared with Whites (114% of expected mortality, P < .001). Clinical trials meeting accrual benchmarks for race included minority authorship., Conclusions: Following the Revitalization Act, minorities and women remain underrepresented in therapeutic clinical trials for neuroepithelial tumors, relative to disease incidence and mortality. Study accrual has improved with time. This study provides a framework for clinical trial accrual efforts and offers guidance regarding workforce considerations associated with enrollment of underserved patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Clinicians have limited time during patient encounters which can result in patients' concerns not being addressed. This study's objective was to test whether an electronic patient-reported outcome quality of life tool (PROQOL) in which patients identify their primary concern during clinic visits improves cancer patient quality of life (QOL)., Patients and Methods: This single center non-blinded prospective clinical trial randomized patients (2:1) to PROQOL versus usual care (UC). Two patient cohorts were enrolled: those with hematologic malignancies (multiple myeloma [MM] or light chain amyloidosis [AL]) and solid tumors (head and neck [H/N] or gynecologic [GYN] malignancies). Primary endpoint was patient-reported QOL at 12 months measured by a single-item Linear Analog Self-Assessment. Value to patients and impact on clinician workflow was measured using a "was it worth it" survey. The study was powered to detect a 0.5 standard deviation difference between groups., Results: Overall 383 patients were enrolled, 171 with MM, 62 AL, 113 GYN, and 37 H/N between July 2016 and April 2018, with 12-month follow-up. There were 171 (44.6%) male patients and median age was 62 years (range 31-87). The most often selected concern was physical health (30.9%), and second was cancer diagnosis and treatment (29.1%). Mean QOL was 7.12 for PROQOL and 6.98 for UC (0-10 scale) at 12 months, with no between-group difference overall (p = 0.56) or within hematologic or solid tumor cohorts, respectively. Among patients, 74% thought the PROQOL tool was worthwhile, 86% would choose PROQOL again, and 81% would recommend it to others. Among clinicians, 95% responded that PROQOL was worthwhile and did not think that PROQOL negatively impacted their workflow., Conclusions: Although we did not demonstrate a QOL difference between PROQOL and UC groups; the PROQOL tool held considerable value in identifying patients' main concerns over time and was worthwhile for patients and clinicians., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Introduction: The European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) measures 15 health-related quality of life (HRQoL) scales relevant to the disease and treatment of patients with cancer. A study by Martinelli (2011) demonstrated that these scales could be grouped into three main clusters: physical, psychological and gastrointestinal. This study aims to validate Martinelli's findings in an independent dataset and evaluate whether these clusters are consistent across cancer types and patient characteristics., Methods: Pre-defined criteria for successful validation were three main clusters should emerge with a minimum R-squared value of 0.51 using pooled baseline-data. A cluster analysis was performed on the 15 QLQ-C30 HRQoL-scales in the overall dataset, as well as by cancer type and selected patient characteristics to examine the robustness of the results., Results: The dataset consisted of 20,066 patients pooled across 17 cancer types. Overall, three main clusters were identified (R 2  = 0.61); physical-cluster included role-functioning, physical-functioning, social-functioning, fatigue, pain, and global-health status; psychological-cluster included emotional-functioning, cognitive-functioning, and insomnia; gastro-intestinal-cluster included nausea/vomiting and appetite loss. The results were consistent across different levels of disease severity, socio-demographic and clinical characteristics with minor variations by cancer type. Global-health status was found to be strongly linked to the scales included in the physical-functioning-related cluster., Conclusion: This study successfully validated prior findings by Martinelli (2011): the QLQ-C30 scales are interrelated and can be grouped into three main clusters. Knowing how these multidimensional HRQoL scales are related to each other can help clinicians and patients with cancer in managing symptom burden, guide policymakers in defining social-support plans and inform selection of HRQoL scales in future clinical trials., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Rice ( Oryza sativa L.) is an important food crop relied upon by billions of people worldwide. However, with increasing pressure from climate change and rapid population growth, cultivation is very water-intensive. Therefore, it is critical to produce rice that is high-yielding and genetically more water-use efficient. Here, using the stabilized fast-neutron mutagenized population of Jao Hom Nin (JHN) - a popular purple rice cultivar - we microscopically examined hundreds of flag leaves to identify four stomatal model mutants with either high density (HD) or low density (LD) stomata, and small-sized (SS) or large-sized (LS) stomata. With similar genetic background and uniformity, the stomatal model mutants were used to understand the role of stomatal variants on physiological responses to abiotic stress. Our results show that SS and HD respond better to increasing CO2 concentration and HD has higher stomatal conductance (gs) compared to the other stomatal model mutants, although the effects on gas exchange or overall plant performance were small under greenhouse conditions. In addition, the results of our drought experiments suggest that LD and SS can better adapt to restricted water conditions, and LD showed higher water use efficiency (WUE) and biomass/plant than other stomatal model mutants under long-term restricted water treatment. Finally, our study suggests that reducing stomata density and size may play a promising role for further work on developing a climate-ready rice variety to adapt to drought and heat stress. We propose that low stomata density and small size have high potential as genetic donors for improving WUE in climate-ready rice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pitaloka, Caine, Hepworth, Harrison, Sloan, Chutteang, Phunthong, Nongngok, Toojinda, Ruengphayak, Arikit, Gray and Vanavichit.)

Background: With increasing molecular analyses of meningiomas, there is a need to harmonize language used to capture clinical data across centers to ensure that molecular alterations are appropriately linked to clinical variables of interest. Here the International Consortium on Meningiomas presents a set of core and supplemental meningioma-specific common data elements (CDEs) to facilitate comparative and pooled analyses., Methods: The generation of CDEs followed the 4-phase process similar to other National Institute of Neurological Disorders and Stroke (NINDS) CDE projects: discovery, internal validation, external validation, and distribution., Results: The CDEs were organized into patient- and tumor-level modules. In total, 17 core CDEs (10 patient level and 7 tumor level) as well as 14 supplemental CDEs (7 patient level and 7 tumor level) were defined and described. These CDEs are now made publicly available for dissemination and adoption., Conclusions: CDEs provide a framework for discussion in the neuro-oncology community that will facilitate data-sharing for collaborative research projects and aid in developing a common language for comparative and pooled analyses. The meningioma-specific CDEs presented here are intended to be dynamic parameters that evolve with time and The Consortium welcomes international feedback for further refinement and implementation of these CDEs., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: We aimed to develop and validate a Compound Quality Score (CQS) as a metric for hospital-level quality of surgical care in kidney cancer at the Veterans Affairs National Health System., Methods: A retrospective review of 8,965 patients with kidney cancer treated at Veterans Affairs (2005-2015) was performed. Two previously validated process quality indicators (QIs) were explored: the proportion of patients with 1) T1a tumors undergoing partial nephrectomy and 2) T1-T2 tumors undergoing minimally invasive radical nephrectomy. Demographics/comorbidity/tumor characteristics/treatment year were used for case mix adjustments at hospital level. The predicted versus observed ratio of cases was calculated per hospital to generate QI scores using indirect standardization and multivariable regression models. CQS represents the sum of both scores. A total of 96 hospitals were grouped by CQS, and short-term patient-level outcomes were regressed on CQS levels to assess for length of stay (LOS), 30-day complications/readmission, 90-day mortality and total cost of surgical admission., Results: CQS identified 25/33/38 hospitals with higher/lower/average performance, respectively. High performance hospitals had higher nephrectomy volumes (p <0.01). Total CQS independently associated with LOS (β=-0.04, p <0.01, predicted LOS 0.84 days shorter for CQS=2 versus CQS=-2), 30-day surgical complications (OR=0.88, p <0.01) or 30-day medical complications (OR=0.93, p <0.01) and total cost of surgical admission (β =-0.014, p <0.01, predicted 12% lower cost for CQS=2 versus CQS=-2). No association was found between CQS and 30-day readmissions or 90-day mortality (all p >0.05), although low event rates were observed (8.9% and 1.7%, respectively)., Conclusions: Variability in quality of surgical care at hospital level can be captured with the CQS among patients with kidney cancer. CQS is associated with relevant short-term perioperative outcomes and surgical cost. QIs should be used to identify, audit and implement quality improvement strategies across health systems.

Atomically thin nanowires (NWs) can be synthesized inside single-walled carbon nanotubes (SWCNTs) and feature unique crystal structures. Here we show that HgTe nanowires formed inside small-diameter (<1 nm) SWCNTs can advantageously alter the optical and electronic properties of the SWCNTs. Metallic purification of the filled SWCNTs was achieved by a gel column chromatography method, leading to an efficient extraction of the semiconducting and metallic portions with known chiralities. Electron microscopic imaging revealed that zigzag HgTe chains were the dominant NW geometry in both the semiconducting and metallic species. Equilibrium-state and ultrafast spectroscopy demonstrated that the coupled electron-phonon system was modified by the encapsulated HgTe NWs, in a way that varied with the chirality. For semiconducting SWCNTs with HgTe NWs, Auger relaxation processes were suppressed, leading to enhanced photoluminescence emission. In contrast, HgTe NWs enhanced the Auger relaxation rate of metallic SWCNTs and created faster phonon relaxation, providing experimental evidence that encapsulated atomic chains can suppress hot carrier effects and therefore boost electronic transport.

The biological and clinical significance of the p.E88del variant in the transcobalamin receptor, CD320, is unknown. This allele is annotated in ClinVar as likely benign, pathogenic, and of uncertain significance. To determine functional consequence and clinical relevance of this allele, we employed cell culture and genetic association studies. Fibroblasts from 16 CD320 p.E88del homozygotes exhibited reduced binding and uptake of cobalamin. Complete ascertainment of newborns with transiently elevated C3 (propionylcarnitine) in New York State demonstrated that homozygosity for CD320 p.E88del was over-represented (7/348, p < 6 × 10 -5 ). Using population data, we estimate that ~85% of the p.E88del homozygotes born in the same period did not have elevated C3, suggesting that cobalamin metabolism in the majority of these infants with this genotype is unaffected. Clinical follow-up of 4/9 homozygous individuals uncovered neuropsychological findings, mostly in speech and language development. None of these nine individuals exhibited perturbation of cobalamin metabolism beyond the newborn stage even during periods of acute illness. Newborns homozygous for this allele in the absence of other factors are at low risk of requiring clinical intervention, although more studies are required to clarify the natural history of various CD320 variants across patient populations., (© 2022 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Adverse events affecting Black patients, including skin hyperpigmentation, may be overlooked using existing clinical trial data on lenalidomide. The objective of this systematic review is to characterize the representation of Black participants and rate of skin hyperpigmentation in clinical trials. In this systematic review and pooled analysis of 21 clinical trials comprising 4539 participants, the proportion of Black participants in trials (6.9%, n = 315) was significantly less than the multiple myeloma population (p < 0.001). The rate of skin hyperpigmentation (0.066%, n = 3) and all skin changes (6.4%, n = 291) was significantly less compared to a 40.8% incidence in a recent retrospective study (p. <0.001). Among participants undergoing treatment with lenalidomide for multiple myeloma, Black patients were underrepresented and the adverse event of skin hyperpigmentation was underreported. Fair representation of Black patients in clinical trials is needed to better describe this adverse event and other events that may be underreported., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Antigen testing using lateral flow devices (LFDs) plays an important role in the management of the novel coronavirus pandemic of 2019 (COVID-19) by rapidly identifying individuals who are asymptomatically carrying high levels of the virus. By January 2021, LFD community testing sites were set up across English local authority areas to support the management and containment of regional COVID-19 cases, initially targeting essential workers unable to work from home during the national lockdown. This study aimed to examine the characteristics and motivations of individuals accessing community LFD testing across two local authority areas (LAAs) in the South West of England., Methods: Data were collected as part of a service evaluation from December 22 nd 2020 until March 15 th 2021 for two LAAs. Demographic and postcode data were collected from an online test appointment booking platform and the National Health Service testing service online system, with data accessed from Public Health England. An online survey was sent to individuals who made a testing appointment at an LAA1 site using the online booking platform, consisting of 12 questions to collect data on individual's motivations for and experiences of testing., Results: Data were available for individuals who completed 12,516 tests in LAA1 and 12,327 tests in LAA2. Most individuals who engaged with testing were female, working age, white, and worked as early years or education staff, health and social care staff, and supermarket or food production staff. 1249 individuals completed the survey with 60% of respondents reported getting tested for work-related reasons. Individuals first heard about LFD testing through various channels including work, media, and word of mouth, and decided to get tested based on the ease and convenience of testing, workplace communications, and to identify asymptomatic cases to help stop the spread. Most tests were completed by individuals living in less deprived areas based on national deciles of deprivation., Conclusions: While national and local COVID-19 testing strategies have evolved, community and personal LFD testing remains a crucial pillar of the testing strategy. Future studies should collect quantitative and qualitative data from residents to most effectively shape testing offers based on the needs and preferences of their population., (© 2022. The Author(s).)

Background: The U.N. health and well-being goals for 2030 focus on maternal and child health outcomes, among others. Challenges to meeting those goals vary widely throughout Nepal owing to the range of sociocultural factors, infrastructural limitations, physical geography and altitudes. This article explores sociocultural and biological influences on fertility and child survival among ethnically Tibetan women in Nepal., Methods: This is a cross sectional study of 430 women, age 46-86 years old, citizens of Nepal and native residents above 3500m in Mustang District, who provided interview and physiological data. Univariate Poisson regression analyses selected significant variables to include in multivariate Poisson regressions investigating the number of pregnancies, livebirths, child survival and death outcomes., Results: Earlier age at first pregnancy, later age at last pregnancy, and miscarriages associated with more pregnancies. Miscarriages and stillbirths associated with fewer livebirths. Higher maternal BMI and FEV6 associated with fewer children dying before age 15. Marital characteristics (status, type, continuity), contraceptive use, relative wealth, and education influenced these covariates., Conclusions: Low maternal pulmonary function and nutritional status predict poorer child survival in Upper Mustang. Addressing poor lung function and nutrition may improve reproductive outcomes among ethnically Tibetan women living at high altitude.

Bombardment of materials by high-energy particles often leads to light emission in a process known as scintillation. Scintillation has widespread applications in medical imaging, x-ray nondestructive inspection, electron microscopy, and high-energy particle detectors. Most research focuses on finding materials with brighter, faster, and more controlled scintillation. We developed a unified theory of nanophotonic scintillators that accounts for the key aspects of scintillation: energy loss by high-energy particles, and light emission by non-equilibrium electrons in nanostructured optical systems. We then devised an approach based on integrating nanophotonic structures into scintillators to enhance their emission, obtaining nearly an order-of-magnitude enhancement in both electron-induced and x-ray-induced scintillation. Our framework should enable the development of a new class of brighter, faster, and higher-resolution scintillators with tailored and optimized performance.

Background: Biliary tract cancers (BTC) have a limited prognosis even for localized cancers, emphasizing the importance of multidisciplinary management. NCCN guidelines recommend adjuvant chemotherapy (CT) +/- radiotherapy (RT) for high-risk disease. We analyzed the association between racial and ethnic category along with other demographic factors and concordance to NCCN guidelines among patients following surgery for high-risk BTC., Methods: Subjects were identified from the National Cancer Database (NCDB) for BTC patients who underwent surgery and found to have metastatic lymph nodes (LN+) or positive surgical margins (M+) from 2004 to 2015. We defined concordance to NCCN guidelines as receiving surgery + CT +/- RT and non-concordance to the guidelines as surgery +/- RT. Descriptive studies and multivariate logistic regression analysis was performed., Results: A total of 3,792 patients were identified with approximately half being female (55.4%) and between the ages of 50-69 (52.8%). Most were White (76.3%) followed by Black (10.6%), Hispanic (8.5%), and Asian (5.3%). The BTC included extrahepatic cholangiocarcinoma (CCA) (48.6%), gallbladder cancer (43.5%), and intrahepatic CCA (7.9%). Most patients had an M- resection (71.9%) but also had LN+ disease (88.0%). There were no significant differences between racial groups in disease presentation (histological grade, tumor stage) and surgical outcomes (LN+, M+, hospital readmission, and 90 day post-surgery mortality). Hispanic patients as compared to White patients were less likely to be insured (85.7% vs 96.3%, p<0.001) and less likely to be treated at an academic facility (42.1% vs 52.1%, p=0.008). Overall, almost one-third (29.7%) of patients received non-concordant NCCN guideline care with Hispanic patients having the highest proportion of non-concordance as compared to Whites patients (36.1% vs 28.7%, p=0.029). On multivariate analysis, Hispanic ethnicity (HR=1.51, 95% CI: 1.15-1.99) remained significantly associated with non-concordance to NCCN guidelines., Conclusion: This study indicates that Hispanic patients with high-risk BTC are significantly less likely to receive NCCN-concordant treatment in comparison to White patients. More research is needed to confirm and understand the observed disparities and guide targeted interventions at the system-level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Hong, Cioffi, Alahmadi, Tang, Ocuin, Patil, Bajor, Saltzman, Mohamed, Selfridge, Webb Hooper, Barnholtz-Sloan and Lee.)

Importance: Nearly 96% of patients with high-grade glioma (HGG) report moderate-to-severe fatigue. Armodafinil is a psychostimulant that might help cancer-related fatigue in patients with HGG., Objective: To determine whether armodafinil reduces fatigue in patients with HGG and moderate-to-severe fatigue., Design, Setting, and Participants: In this randomized multicenter, phase 3, double-blinded, placebo-controlled clinical trial, adults with HGG and moderate-to-severe fatigue who were clinically stable at least 4 weeks after completing radiation therapy were randomized to receive armodafinil daily (150 mg or 250 mg) or placebo over 8 weeks. A score of at least 6 out of 10 on severity scale for the brief fatigue inventory scale, with 10 being the worst, was required to suggest moderate-to-severe fatigue. Patients were allowed stable doses of corticosteroids but were excluded if they required increasing amounts of corticosteroids, were receiving some other treatment for fatigue, or had an uncontrolled seizure disorder. The study was conducted from June 2013 to December 15, 2019., Interventions: Patients were randomized to 150 mg of armodafinil, 250 mg of armodafinil, or placebo for a total of 8 weeks with assessments at weeks 4 and 8., Main Outcomes and Measures: The primary outcome was efficacy in treating cancer-related fatigue. Secondary outcomes included safety, neurocognitive function, and quality of life. Patients were evaluated at baseline and at weeks 4 and 8. Efficacy between the placebo and the 2 doses of study drug was determined by an improvement by 2 points on the 0 to 10 brief fatigue inventory scale. Kruskal-Wallis and χ2 tests were used and followed by confirmatory analyses., Results: A total of 328 patients were enrolled, of whom 297 had evaluable end point data. Of these, 103 received 150 mg of armodafinil (mean [SD] age, 58.5 [11.9] years; 42 women [40.8%]), 97 250 mg of armodafinil (mean [SD] age, 56.6 [12.5] years; 37 women [38.1%]), and 97 placebo (mean [SD] age, 57.1 [12.5] years; 39 women [40.2%]). There was no difference in the proportion of patients who achieved clinically meaningful fatigue reduction between arms (28% [95% CI 20%-30%] for 150 mg of armodafinil, 28% [95% CI 19%-38%] for 250 mg of armodafinil, and 30% [95% CI 21%-40%] for placebo). There was a statistically significant reduction in global fatigue for corticosteroid users compared with nonusers (-0.7 [95% CI, -1.5 to -0.3] vs -1.7 [95% CI, -2.1 to -1.3]; P < .001). More patients (2 vs 7) reported insomnia with treatment with 250 mg of armodafinil., Conclusions and Relevance: The results of this randomized clinical trial found no meaningful benefit of using treatment with armodafinil to reduce cancer-related fatigue in patients with HGG., Trial Registration: ClinicalTrials.gov Identifier: NCT01781468.

Study of human monocytic Myeloid-Derived Suppressor cells Mo-MDSC (CD14 + HLA-DR neg/low ) has been hampered by the lack of positive cell-surface markers. In order to identify positive markers for Mo-MDSC, we performed microarray analysis comparing Mo-MDSC cells from healthy subjects versus CD14 + HLA-DR high monocytes. We have identified the surface ectoenzyme Vanin-2(VNN2) protein as a novel biomarker highly-enriched in healthy subjects Mo-MDSC. Indeed, healthy subjects Mo-MDSC cells expressed 68 % VNN2, whereas only 9% VNN2 expression was observed on CD14 + HLA-DR high cells (n = 4 p < 0.01). The top 10 percent positive VNN2 monocytes expressed CD33 and CD11b while being negative for HLA-DR, CD3, CD15, CD19 and CD56, consistent with a Mo-MDSC phenotype. CD14 + VNN2 high monocytes were able to inhibit CD8 T cell proliferation comparably to traditional Mo-MDSC at 51 % and 48 % respectively. However, VNN2 expression on CD14 + monocytes from glioma patients was inversely correlated to their grade. CD14 + VNN2 high monocytes thus appear to mark a monocytic population similar to Mo-MDSC only in healthy subjects, which may be useful for tumor diagnoses., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The identification of hereditary cancer genes for esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), may prove critical for the development of novel prevention and treatment strategies. Specifically, efforts for detecting BE and EAC susceptibility genes have focused on families with three or more affected members, since these individuals have an earlier age onset compared to non-familial individuals. Given that the use of BE may overestimate the likelihood of disease heritability, we evaluated the age of diagnosis in kindreds with a restricted definition including only confirmed high-grade dysplasia (HGD) or EAC. The Familial Barrett's Esophagus Consortium database was used to identify individuals with HGD and EAC. These individuals were subsequently split into three kindred groups: non-familial-a single affected family member, duplex-two affected family members, and multiplex-three or more affected family members. Age of cancer diagnosis and other risk factors were compared between individuals in these groups. The study included 441 non-familial, 46 duplex, and 13 multiplex individuals. There was a statistically significant difference for age of diagnosis for individuals in the multiplex families compared to the non-familial and duplex families (56.0 versus 64.3, 63.5; p = 0.049). There was no significant difference between demographic factors and other cancer risk factors between family types. The results of this study support a genetic basis for familial Barrett's associated neoplasia and evaluation of the genetic susceptibility to this disease should continue to focus on families with multiple (three or more) affected members., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)