Accuracy of a Continuous Glucose Monitor in the Intensive Care Unit: A Proposed Accuracy Standard and Calibration Protocol for Inpatient Use.

Background and Aims: Guidelines now recommend inpatient continuous glucose monitor (CGM) use with confirmatory blood glucose measurements. However, the Food and Drug Administration has not yet officially approved CGM for inpatient use in large part because its accuracy has not been established in this setting. We tested the accuracy of the Dexcom G6 (G6) in 28 adults on an insulin infusion in a medical-surgical intensive care unit with 1064 matched CGM and arterial point-of-care pairs. Methods: The participants were on average 57.29 (SD 2.39) years, of whom 13 had a prior diagnosis of diabetes and 14 were admitted for a surgical diagnosis. The first 19 participants received the G6 without calibration and had a mean absolute relative difference (MARD) of 13.19% (IQR 5.11, 19.03) across 659 matched pairs, which just meets the critical care expert recommendation of MARD <14%. We then aimed to improve accuracy for the subsequent 9 participants using a calibration protocol. Results: The MARD for calibrated participants was 9.65% (3.03, 13.33), significantly lower than for uncalibrated participants (P < 0.001). Calibration also demonstrated excellent safety with 100% of values within the Clarke Error Grid zones A and B compared with 99.07% without calibration. Our protocol achieved the lowest MARD and safest CEG profile in the critical care setting and well exceeds the critical care expert recommendations. Our large sample of heterogenous critically ill patients also reached comparable accuracy to the MARD of 9% for G6 in outpatients. We believe our calibration protocol will allow G6 to be used with sufficient accuracy in inpatients.

The presence of polycystic ovary syndrome increases the risk of maternal but not neonatal complications in women with type 2 diabetes in pregnancy.

AIMS: Our aims were, in the setting of type 2 diabetes mellitus (T2DM) in pregnancy, to investigate the association of polycystic ovary syndrome (PCOS) with perinatal outcomes and to examine whether treatment with metformin had a differential effect in those with and without PCOS. MATERIALS AND METHODS: We performed a retrospective cohort study using the metformin in women with type 2 diabetes in pregnancy (MiTy) trial data. We examined differences in maternal and neonatal outcomes among MiTy participants with and without PCOS using linear and logistic regression to adjust for potential confounders. We additionally examined the relative difference in the effect of metformin treatment on pregnancy outcomes among MiTy participants with PCOS versus those without PCOS. RESULTS: Among women with T2DM in pregnancy, PCOS was significantly associated with higher excess gestational weight gain (unadjusted 12.0 vs. 11.4 kg, adjusted mean difference 2.1 kg [0.3, 3.9], p = 0.021) and higher total insulin dose at 34-36 weeks (unadjusted 172 vs. 124 units per day, adjusted mean difference 44 units [15, 73], p = 0.004), but no difference was seen in neonatal outcomes. Unlike the non-PCOS subgroup, metformin treatment versus placebo in the PCOS subgroup was associated with an increase in extremely large-for-gestational-age infants (28.6 vs. 14.0%, p = 0.008 for interaction) and an increase in worsened pre-existing maternal hypertension (16.7 vs. 4.5%, p = 0.046 for interaction). CONCLUSIONS: Clinicians should be alerted to the potential for high insulin requirements and excess weight gain in pregnant patients with T2DM and comorbid PCOS. Moreover, metformin may not be as beneficial in this population as previously understood.

Lunar eclipses illuminate timing and climate impact of medieval volcanism.

Explosive volcanism is a key contributor to climate variability on interannual to centennial timescales1. Understanding the far-field societal impacts of eruption-forced climatic changes requires firm event chronologies and reliable estimates of both the burden and altitude (that is, tropospheric versus stratospheric) of volcanic sulfate aerosol2,3. However, despite progress in ice-core dating, uncertainties remain in these key factors4. This particularly hinders investigation of the role of large, temporally clustered eruptions during the High Medieval Period (HMP, 1100-1300 CE), which have been implicated in the transition from the warm Medieval Climate Anomaly to the Little Ice Age5. Here we shed new light on explosive volcanism during the HMP, drawing on analysis of contemporary reports of total lunar eclipses, from which we derive a time series of stratospheric turbidity. By combining this new record with aerosol model simulations and tree-ring-based climate proxies, we refine the estimated dates of five notable eruptions and associate each with stratospheric aerosol veils. Five further eruptions, including one responsible for high sulfur deposition over Greenland circa 1182 CE, affected only the troposphere and had muted climatic consequences. Our findings offer support for further investigation of the decadal-scale to centennial-scale climate response to volcanic eruptions.

Multilevel cultural evolution: From new theory to practical applications.

Evolutionary science has led to many practical applications of genetic evolution but few practical uses of cultural evolution. This is because the entire study of evolution was gene centric for most of the 20th century, relegating the study and application of human cultural change to other disciplines. The formal study of human cultural evolution began in the 1970s and has matured to the point of deriving practical applications. We provide an overview of these developments and examples for the topic areas of complex systems science and engineering, economics and business, mental health and well-being, and global change efforts.

Identification of an integrase-independent pathway of retrotransposition.

Retroviruses and long terminal repeat retrotransposons rely on integrase (IN) to insert their complementary DNA (cDNA) into the genome of host cells. Nevertheless, in the absence of IN, retroelements can retain notable levels of insertion activity. We have characterized the IN-independent pathway of Tf1 and found that insertion sites had homology to the primers of reverse transcription, which form single-stranded DNAs at the termini of the cDNA. In the absence of IN activity, a similar bias was observed with HIV-1. Our studies showed that the Tf1 insertions result from single-strand annealing, a noncanonical form of homologous recombination mediated by Rad52. By expanding our analysis of insertions to include repeat sequences, we found most formed tandem elements by inserting at preexisting copies of a related transposable element. Unexpectedly, we found that wild-type Tf1 uses the IN-independent pathway as an alternative mode of insertion.

Inhaled Medicines: Past, Present, and Future.

The purpose of this review is to summarize essential pharmacological, pharmaceutical, and clinical aspects in the field of orally inhaled therapies that may help scientists seeking to develop new products. After general comments on the rationale for inhaled therapies for respiratory disease, the focus is on products approved approximately over the last half a century. The organization of these sections reflects the key pharmacological categories. Products for asthma and chronic obstructive pulmonary disease include ß -2 receptor agonists, muscarinic acetylcholine receptor antagonists, glucocorticosteroids, and cromones as well as their combinations. The antiviral and antibacterial inhaled products to treat respiratory tract infections are then presented. Two "mucoactive" products-dornase α and mannitol, which are both approved for patients with cystic fibrosis-are reviewed. These are followed by sections on inhaled prostacyclins for pulmonary arterial hypertension and the challenging field of aerosol surfactant inhalation delivery, especially for prematurely born infants on ventilation support. The approved products for systemic delivery via the lungs for diseases of the central nervous system and insulin for diabetes are also discussed. New technologies for drug delivery by inhalation are analyzed, with the emphasis on those that would likely yield significant improvements over the technologies in current use or would expand the range of drugs and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of approved orally inhaled drug products for a variety of respiratory diseases and for systemic administration should be helpful in making judicious decisions about the development of new or improved inhaled drugs. These aspects include the choices of the active ingredients, formulations, delivery systems suitable for the target patient populations, and, to some extent, meaningful safety and efficacy endpoints in clinical trials.

Analyzing Plant Gene Targeting Outcomes and Conversion Tracts with Nanopore Sequencing.

The high-throughput molecular analysis of gene targeting (GT) events is made technically challenging by the residual presetabce of donor molecules. Large donor molecules restrict primer placement, resulting in long amplicons that cannot be readily analyzed using standard NGS pipelines or qPCR-based approaches such as ddPCR. In plants, removal of excess donor is time and resource intensive, often requiring plant regeneration and weeks to months of effort. Here, we utilized Oxford Nanopore Amplicon Sequencing (ONAS) to bypass the limitations imposed by donor molecules with 1 kb of homology to the target and dissected GT outcomes at three loci in Nicotiana benthamia leaves. We developed a novel bioinformatic pipeline, Phased ANalysis of Genome Editing Amplicons (PANGEA), to reduce the effect of ONAS error on amplicon analysis and captured tens of thousands of somatic plant GT events. Additionally, PANGEA allowed us to collect thousands of GT conversion tracts 5 days after reagent delivery with no selection, revealing that most events utilized tracts less than 100 bp in length when incorporating an 18 bp or 3 bp insertion. These data demonstrate the usefulness of ONAS and PANGEA for plant GT analysis and provide a mechanistic basis for future plant GT optimization.

Falsely elevated serum estradiol due to heterophile antibody interference: a case report

SUMMARY Falsely elevated estradiol is rare, may result from heterophile antibody interference, and can result in unnecessary investigation and intervention. We present the case of a 56-year-old female with falsely elevated estradiol levels inconsistent with her overall clinical picture, which ultimately led to an unnecessary surgical procedure. With the use of alternative analytical platforms and a heterophile antibody blocking agent, we determined the false elevation was due to heterophile antibody interference. Clinicians must suspect and investigate for laboratory error when the clinical picture contradicts laboratory results.

Fine Mapping of Leaf Trichome Density Revealed a 747-kb Region on Chromosome 1 in Cold-Hardy Hybrid Wine Grape Populations.

Segregation for leaf trichome density was observed in a cold-hardy hybrid grape population GE1025 (N = ∼125, MN1264 × MN1246) that was previously used to detect a quantitative trait locus (QTL) underlying foliar phylloxera resistance on chromosome 14. Our hypothesis was that high trichome density was associated with resistance to phylloxera. Existing literature found trichome density QTL on chromosomes 1 and 15 using a hybrid grape population of "Horizon" × Illinois 547-1 and suggested a few candidate genes. To validate the reported QTL and our hypothesis, interval mapping was conducted in GE1025 with previous genotyping-by-sequencing (GBS) single nucleotide polymorphism (SNP) genotype data and phenotypic scores collected using a 0-6 trichome density scale at several leaf positions. Evaluations were done on replicated forced dormant cuttings in 2 years and on field-grown leaves in 1 year. There was no strong relationship between trichome density and phylloxera resistance except for a Pearson's correlation (r) of about -0.2 between a few trichome density traits and phylloxera severity traits at 2 and 3 weeks after infestation. Two genetic regions were repeatedly detected for multiple trichome density traits: from 10 to 20.7 Mbp (∼10 Mbp) on chromosome 1 for ribbon and simple density traits and from 2.4 to 8.9 Mbp on chromosome 10 for ribbon density traits, explaining 12.1-48.2 and 12.6-27.5% of phenotypic variation, respectively. To fine map, we genotyped a larger population, GE1783 (N = ∼1,023, MN1264 × MN1246), with conserved rhAmpSeq haplotype markers across multiple Vitis species and phenotyped 233 selected potential recombinants. Evaluations were conducted on field-grown leaves in a single year. The QTL for ribbon trichome density on adaxial vein and adaxial leaf and simple density on abaxial vein was fine mapped to 12.63-13.38 Mbp (747 kb) on chromosome 1. We found variations of MN1264 and MN1246 at candidate genes NAC transcription factor 29, EF-hand protein, and MYB140 in this region and three other surrounding candidate genes proposed previously. Even though no strong relationship between foliar phylloxera resistance and trichome density was found, this study validated and fine mapped a major QTL for trichome density using a cold-hardy hybrid grape population and shed light on a few candidate genes that have implications for different breeding programs.

Falsely elevated serum estradiol due to heterophile antibody interference: a case report.

Falsely elevated estradiol is rare, may result from heterophile antibody interference, and can result in unnecessary investigation and intervention. We present the case of a 56-year-old female with falsely elevated estradiol levels inconsistent with her overall clinical picture, which ultimately led to an unnecessary surgical procedure. With the use of alternative analytical platforms and a heterophile antibody blocking agent, we determined the false elevation was due to heterophile antibody interference. Clinicians must suspect and investigate for laboratory error when the clinical picture contradicts laboratory results.

Common asset trusts to effectively steward natural capital and ecosystem services at multiple scales.

Ecosystems (natural capital) produce a range of benefits to humans. Natural capital is best thought of as common property since many of the ecosystem services it helps produce are non-rival and/or non-excludable. Private property regimes and markets alone are ineffective and inappropriate institutions to manage them sustainably. These systems can be better managed as commons, using more nuanced private and community property rights and Common Asset Trusts (CATs), with legal precedent in the Public Trust Doctrine. Effective CATs embody a generalized version of Elinore Ostrom's eight core design principles for sustainable commons management: (1) shared identity and purpose; (2) equitable distribution of contributions and benefits; (3) fair and inclusive decision-making; (4) monitoring agreed behaviours; (5) graduated responses; (6) fast and fair conflict resolution; (7) authority to self-govern; and (8) collaborative relations with other groups and spatial scales. Here, we describe a few existing and proposed systems that approximate effective CATs. We also suggest how Costa Rica can transform its existing payment for ecosystem services (PES) scheme into a national CAT. Finally, we describe how CATs can facilitate more fair and effective public/private partnerships (PPPs) to invest in natural capital and ecosystem services.

Primary and Ipilimumab-induced Hypophysitis: A Single-center Case Series.

PURPOSE: To present a case series of primary and immunotherapy-related secondary hypophysitis. METHODS: A single-center retrospective chart review was performed at the University of British Columbia, Vancouver, Canada. Eleven cases of primary hypophysitis and 2 cases of immunotherapy-related secondary hypophysitis were included. Of the 11 primary cases, 6 were diagnosed clinically without biopsy. RESULTS: In primary hypophysitis, headache was the most common presenting symptom (6/11; 55%) and stalk enlargement the prevailing radiologic sign (8/11; 73%). Central adrenal insufficiency (4/11; 36%), central hypothyroidism (4/11; 36%), and central diabetes insipidus (CDI) (4/11; 36%) were the most common pituitary deficiencies at presentation. Initial management included surgery (4/11; 36%), supraphysiologic steroids (2/11; 18%), or observation (6/11; 55%). Outcomes assessed included radiologic improvement (8/9; 89%), improvement in mass symptoms (4/7; 57%), anterior pituitary recovery (1/7; 14%), and CDI recovery (0/4; 0%). In immunotherapy-related hypophysitis either under observation or supraphysiologic steroid therapy, the inflammatory mass resolved and pituitary dysfunction persisted. CONCLUSIONS: In primary hypophysitis, the inflammatory pituitary mass typically resolves and hypopituitarism persists. In the absence of severe or progressive neurologic deficits, a presumptive clinical diagnosis and conservative medical management should be attempted. In the absence of severe features, immunotherapy-related hypophysitis may be managed effectively without the use of supraphysiologic steroids.

Core design principles for nurturing organization-level selection.

Dynamic relationships between individuals and groups have been a focus for evolutionary theorists and modelers for decades. Among evolutionists, selfish gene theory promotes reductionist approaches while multilevel selection theory encourages a context-sensitive approach that appreciates that individuals and groups can both matter. Among economists, a comparable contrast is found wherein the reductionist shareholder primacy theory most associated with Nobel laureate Milton Friedman is very different from the context-sensitive focus on managing common resources that Nobel laureate Elinor Ostrom pioneered. In this article, we examine whether the core design principles that Ostrom advanced can cultivate selection at supra-individual levels across different domains. We show that Ostrom's design principles that were forged in the context of managing natural resources are associated with positive outcomes for human social groups across a variety of functional domains.

Overcoming bottlenecks in plant gene editing.

Agriculture has reached a technological inflection point. The development of novel gene editing tools and methods for their delivery to plant cells promises to increase genome malleability and transform plant biology. Whereas gene editing is capable of making a myriad of DNA sequence modifications, its widespread adoption has been hindered by a number of factors, particularly inefficiencies in creating precise DNA sequence modifications and ineffective methods for delivering gene editing reagents to plant cells. Here, we briefly overview the principles of plant genome editing and highlight a subset of the most recent advances that promise to overcome current limitations.

Increased carotid plaque burden in patients with family medical history of premature cardiovascular events in the absence of classical risk factors.

INTRODUCTION: The hypothesis that relates atherosclerosis to traditional risk factors (TRF) seems to be not as adequate as previously thought; other risk factors (RF) need to be considered to prevent atherosclerosis progression. Although a family medical history of premature cardiovascular events (FHx) has been considered the putative RF for decades, it has not been incorporated routinely into cardiovascular risk evaluation along with another RF. The objective of this study was to investigate whether FHx is associated with a higher atherosclerotic burden, measured as carotid total plaque area (TPA) in a population having no traditional RF. MATERIAL AND METHODS: The study included 4,351 primary care patients in Argentina. After excluding a personal history of cardiovascular disease (CVD) and TRF: hypertension, diabetes mellitus, hypercholesterolemia, smoking history, and body mass index (BMI) > 25 kg/cm2, 34 patients with FHx were identified. Compared to 56 matched controls TPA was 86% higher in FHx patients (p < 0.05). A second analysis performed in hypertensive patients but no other TRF; 32 patients with FHx were identified. RESULTS: Compared with 44 matched controls, TPA was 77% higher in FHx patients (p < 0.05). A final analysis using a generalized linear model with TPA progression as the response variable suggests that TPA progresses more rapidly in FHx patients compared to controls. CONCLUSIONS: The FHx was associated with increased TPA burden and progression in the absence of other TRF. This supports ultrasound screening in FHx patients in order to detect high-risk patients who may benefit from early intervention.

Does your mindfulness benefit others? A systematic review and meta-analysis of the link between mindfulness and prosocial behaviour.

Mindfulness-based meditation practices have received substantial scientific attention in recent years. Mindfulness has been shown to bring many psychological benefits to the individual, but much less is known about whether these benefits extend to others. This meta-analysis reviewed the link between mindfulness - as both a personality variable and an intervention - and prosocial behaviour. A literature search produced 31 eligible studies (N = 17,241) and 73 effect sizes. Meta-analyses were conducted using mixed-effects structural equation models to examine pooled effects and potential moderators of these effects. We found a positive pooled effect between mindfulness and prosocial behaviour for both correlational (d = .73 CI 95% [0.51 to 0.96]) and intervention studies (d = .51 CI 95% [0.37 to 0.66]). For the latter, medium-sized effects were obtained across varying meditation types and intensities, and across gender and age categories. Preliminary evidence is presented regarding potential mediators of these effects. Although we found that mindfulness is positively related to prosociality, further research is needed to examine the mediators of this link and the contexts in which it is most pronounced.

Departing from the essential features of a high quality systematic review of psychotherapy: A response to Öst (2014) and recommendations for improvement.

Öst's (2014) systematic review and meta-analysis of Acceptance and Commitment Therapy (ACT) has received wide attention. On the basis of his review, Öst argued that ACT research was not increasing in its quality and that, in contradiction to the views of Division 12 of the American Psychological Association (APA), ACT is "not yet well-established for any disorder" (2014, p. 105). We conducted a careful examination of the methods, approach, and data used in the meta-analysis. Based in part on examinations by the authors of the studies involved, which were then independently checked, 91 factual or interpretive errors were documented, touching upon 80% of the studies reviewed. Comparisons of Öst's quality ratings with independent teams rating the same studies with the same scale suggest that Ost's ratings were unreliable. In all of these areas (factual errors; interpretive errors; quality ratings) mistakes and differences were not random: Ost's data were dominantly more negative toward ACT. The seriousness, range, and distribution of errors, and a wider pattern of misinterpreting the purpose of studies and ignoring positive results, suggest that Öst's review should be set aside in future considerations of the evidence base for ACT. We argue that future published reviews and meta-analyses should rely upon diverse groups of scholars rather than a single individual; that resulting raw data should be made available for inspection and independent analysis; that well-crafted committees rather than individuals should design, apply and interpret quality criteria; that the intent of transdiagnostic studies need to be more seriously considered as the field shifts away from a purely syndromal approach; and that data that demonstrate theoretically consistent mediating processes should be given greater weight in evaluating specific interventions. Finally, in order to examine substantive progress since Öst's review, recent outcome and process evidence was briefly examined.

Validating Genome-Wide Association Candidates Controlling Quantitative Variation in Nodulation.

Genome-wide association (GWA) studies offer the opportunity to identify genes that contribute to naturally occurring variation in quantitative traits. However, GWA relies exclusively on statistical association, so functional validation is necessary to make strong claims about gene function. We used a combination of gene-disruption platforms (Tnt1 retrotransposons, hairpin RNA-interference constructs, and CRISPR/Cas9 nucleases) together with randomized, well-replicated experiments to evaluate the function of genes that an earlier GWA study in Medicago truncatula had identified as candidates contributing to variation in the symbiosis between legumes and rhizobia. We evaluated ten candidate genes found in six clusters of strongly associated single nucleotide polymorphisms, selected on the basis of their strength of statistical association, proximity to annotated gene models, and root or nodule expression. We found statistically significant effects on nodule production for three candidate genes, each validated in two independent mutants. Annotated functions of these three genes suggest their contributions to quantitative variation in nodule production occur through processes not previously connected to nodulation, including phosphorous supply and salicylic acid-related defense response. These results demonstrate the utility of GWA combined with reverse mutagenesis technologies to discover and validate genes contributing to naturally occurring variation in quantitative traits. The results highlight the potential for GWA to complement forward genetics in identifying the genetic basis of ecologically and economically important traits.

Cognitive Defusion Predicts More Approach and Less Avoidance Coping With Stress, Independent of Threat and Self-Efficacy Appraisals.

OBJECTIVE: Recent evidence suggests that the way in which individuals relate to their aversive thoughts predicts behavioral effectiveness more than the content of such thoughts. This article is among the first to explore whether this is true for coping with stressful events. METHOD: Three studies with emerging adults (Study 1, N = 202) and adults (Study 2, N = 201; Study 3, N = 141) tested whether changes in how individuals relate to their stress-related thoughts, measured using the individual-difference construct of cognitive defusion, predicted more approach and less avoidance coping behavior, controlling for stress-related appraisals. RESULTS: We found that cognitive defusion predicted more approach coping (Studies 1 and 3) and less avoidance coping (Studies 2 and 3) following laboratory-induced stress (Study 1), naturally occurring monthly stress (Study 2), and daily stress (Study 3). These effects occurred independently of the effects of threat appraisals (Studies 1-3) and self-efficacy appraisals (Study 3) on coping responses. CONCLUSIONS: Cognitive defusion may be an important individual-difference predictor of coping behavior, adding to established theories of coping such as Lazarus and Folkman's (1987) transactional theory.