700,000 years of tropical Andean glaciation.

Our understanding of the climatic teleconnections that drove ice-age cycles has been limited by a paucity of well-dated tropical records of glaciation that span several glacial-interglacial intervals. Glacial deposits offer discrete snapshots of glacier extent but cannot provide the continuous records required for detailed interhemispheric comparisons. By contrast, lakes located within glaciated catchments can provide continuous archives of upstream glacial activity, but few such records extend beyond the last glacial cycle. Here a piston core from Lake Junín in the uppermost Amazon basin provides the first, to our knowledge, continuous, independently dated archive of tropical glaciation spanning 700,000 years. We find that tropical glaciers tracked changes in global ice volume and followed a clear approximately 100,000-year periodicity. An enhancement in the extent of tropical Andean glaciers relative to global ice volume occurred between 200,000 and 400,000 years ago, during sustained intervals of regionally elevated hydrologic balance that modified the regular approximately 23,000-year pacing of monsoon-driven precipitation. Millennial-scale variations in the extent of tropical Andean glaciers during the last glacial cycle were driven by variations in regional monsoon strength that were linked to temperature perturbations in Greenland ice cores1; these interhemispheric connections may have existed during previous glacial cycles.

Geographic disparities in performance of pediatric polysomnography to diagnose obstructive sleep apnea in a universal access health care system.

BACKGROUND: Diagnostic polysomnography (PSG) is recommended prior to adenotonsillectomy (AT) for children with obstructive sleep apnea (OSA) and certain high-risk characteristics, but resource limitations often prevent this practice. OBJECTIVE: We performed a population-based assessment of children across Ontario, Canada to describe and quantify disparities in PSG. METHODS AND MATERIALS: This retrospective cohort study was performed using provincial health administrative data held at ICES. We identified children 0-10 years old who underwent PSG and AT between 2009 and 2018, and those with a PSG within 18 months prior to and/or 12 months following AT. We calculated the odds of PSG prior to/following AT after adjustment for demographics, medical comorbidities, geographic and socioeconomic characteristics. Our main predictor was driving time/distance to the nearest pediatric sleep centre ascertained using spatial analysis and geographic information systems. RESULTS: We identified 27,837 children <10 years old who underwent AT for OSA in Ontario. Only 12.8% had a PSG within 18 months prior and 5.7% had a PSG within 12 months following AT. Shorter driving time/distance, older age, male sex and certain comorbidities were associated with increased odds of PSG. CONCLUSION: Only a small proportion of children in our cohort underwent PSG prior to or following AT surgery despite universal access to healthcare. This study suggests a need to increase overall PSG access, particularly for those living distant from existing pediatric sleep centres. Future studies could determine if increased PSG testing in 'underserviced areas' would reduce overall surgery rates and/or improve health outcomes.

InterCarb: A Community Effort to Improve Interlaboratory Standardization of the Carbonate Clumped Isotope Thermometer Using Carbonate Standards.

Increased use and improved methodology of carbonate clumped isotope thermometry has greatly enhanced our ability to interrogate a suite of Earth-system processes. However, interlaboratory discrepancies in quantifying carbonate clumped isotope (Δ47) measurements persist, and their specific sources remain unclear. To address interlaboratory differences, we first provide consensus values from the clumped isotope community for four carbonate standards relative to heated and equilibrated gases with 1,819 individual analyses from 10 laboratories. Then we analyzed the four carbonate standards along with three additional standards, spanning a broad range of δ47 and Δ47 values, for a total of 5,329 analyses on 25 individual mass spectrometers from 22 different laboratories. Treating three of the materials as known standards and the other four as unknowns, we find that the use of carbonate reference materials is a robust method for standardization that yields interlaboratory discrepancies entirely consistent with intralaboratory analytical uncertainties. Carbonate reference materials, along with measurement and data processing practices described herein, provide the carbonate clumped isotope community with a robust approach to achieve interlaboratory agreement as we continue to use and improve this powerful geochemical tool. We propose that carbonate clumped isotope data normalized to the carbonate reference materials described in this publication should be reported as Δ47 (I-CDES) values for Intercarb-Carbon Dioxide Equilibrium Scale.

Lattice QCD Equation of State at Finite Chemical Potential from an Alternative Expansion Scheme.

In this Letter, we introduce a novel scheme for extrapolating the equation of state of QCD to finite chemical potential that features considerably improved convergence properties and allows us to extend its reach to unprecedentedly high baryonic chemical potentials. We present continuum extrapolated lattice results for the new expansion coefficients and show the thermodynamic observables up to µ_{B}/T≤3.5. This novel expansion does not suffer from the shortcomings that characterize the traditional Taylor expansion method, such as difficulties inherent in performing such an expansion with a limited number of coefficients and the poor signal-to-noise ratio that affects Taylor coefficients determined from lattice calculations.

Leading hadronic contribution to the muon magnetic moment from lattice QCD.

The standard model of particle physics describes the vast majority of experiments and observations involving elementary particles. Any deviation from its predictions would be a sign of new, fundamental physics. One long-standing discrepancy concerns the anomalous magnetic moment of the muon, a measure of the magnetic field surrounding that particle. Standard-model predictions1 exhibit disagreement with measurements2 that is tightly scattered around 3.7 standard deviations. Today, theoretical and measurement errors are comparable; however, ongoing and planned experiments aim to reduce the measurement error by a factor of four. Theoretically, the dominant source of error is the leading-order hadronic vacuum polarization (LO-HVP) contribution. For the upcoming measurements, it is essential to evaluate the prediction for this contribution with independent methods and to reduce its uncertainties. The most precise, model-independent determinations so far rely on dispersive techniques, combined with measurements of the cross-section of electron-positron annihilation into hadrons3-6. To eliminate our reliance on these experiments, here we use ab initio quantum chromodynamics (QCD) and quantum electrodynamics simulations to compute the LO-HVP contribution. We reach sufficient precision to discriminate between the measurement of the anomalous magnetic moment of the muon and the predictions of dispersive methods. Our result favours the experimentally measured value over those obtained using the dispersion relation. Moreover, the methods used and developed in this work will enable further increased precision as more powerful computers become available.

Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) through non-specialist providers and telemedicine: a study protocol for a non-inferiority randomized controlled trial.

BACKGROUND: Depression and anxiety impact up to 1 in 5 pregnant and postpartum women worldwide. Yet, as few as 20% of these women are treated with frontline interventions such as evidence-based psychological treatments. Major barriers to uptake are the limited number of specialized mental health treatment providers in most settings, and problems with accessing in-person care, such as childcare or transportation. Task sharing of treatment to non-specialist providers with delivery on telemedicine platforms could address such barriers. However, the equivalence of these strategies to specialist and in-person models remains unproven. METHODS: This study protocol outlines the Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) randomized trial. SUMMIT is a pragmatic, non-inferiority test of the comparable effectiveness of two types of providers (specialist vs. non-specialist) and delivery modes (telemedicine vs. in-person) of a brief, behavioral activation (BA) treatment for perinatal depressive and anxiety symptoms. Specialists (psychologists, psychiatrists, and social workers with ≥ 5 years of therapy experience) and non-specialists (nurses and midwives with no formal training in mental health care) were trained in the BA protocol, with the latter supervised by a BA expert during treatment delivery. Consenting pregnant and postpartum women with Edinburgh Postnatal Depression Scale (EPDS) score of ≥ 10 (N = 1368) will be randomized to one of four arms (telemedicine specialist, telemedicine non-specialist, in-person specialist, in-person non-specialist), stratified by pregnancy status (antenatal/postnatal) and study site. The primary outcome is participant-reported depressive symptoms (EPDS) at 3 months post-randomization. Secondary outcomes are maternal symptoms of anxiety and trauma symptoms, perceived social support, activation levels and quality of life at 3-, 6-, and 12-month post-randomization, and depressive symptoms at 6- and 12-month post-randomization. Primary analyses are per-protocol and intent-to-treat. The study has successfully continued despite the COVID-19 pandemic, with needed adaptations, including temporary suspension of the in-person arms and ongoing randomization to telemedicine arms. DISCUSSION: The SUMMIT trial is expected to generate evidence on the non-inferiority of BA delivered by a non-specialist provider compared to specialist and telemedicine compared to in-person. If confirmed, results could pave the way to a dramatic increase in access to treatment for perinatal depression and anxiety. TRIAL REGISTRATION: ClinicalTrials.gov NCT04153864 . Registered on November 6, 2019.

Cost-effectiveness of prenatal screening methods for congenital heart defects in pregnancies conceived by in-vitro fertilization.

OBJECTIVES: To determine if a policy of universal fetal echocardiography (echo) in pregnancies conceived by in-vitro fertilization (IVF) is cost-effective as a screening strategy for congenital heart defects (CHDs) and to examine the cost-effectiveness of various other CHD screening strategies in IVF pregnancies. METHODS: A decision-analysis model was designed from a societal perspective with respect to the obstetric patient, to compare the cost-effectiveness of three screening strategies: (1) anatomic ultrasound (US): selective fetal echo following abnormal cardiac findings on detailed anatomic survey; (2) intracytoplasmic sperm injection (ICSI) only: fetal echo for all pregnancies following IVF with ICSI; (3) all IVF: fetal echo for all IVF pregnancies. The model initiated at conception and had a time horizon of 1 year post-delivery. The sensitivities and specificities for each strategy, the probabilities of major and minor CHDs and all other clinical estimates were derived from the literature. Costs, including imaging, consults, surgeries and caregiver productivity losses, were derived from the literature and Medicare databases, and are expressed in USA dollars ($). Effectiveness was quantified as quality-adjusted life years (QALYs), based on how the strategies would affect the quality of life of the obstetric patient. Secondary effectiveness was quantified as number of cases of CHD and, specifically, cases of major CHD, detected. RESULTS: The average base-case cost of each strategy was as follows: anatomic US, $8119; ICSI only, $8408; and all IVF, $8560. The effectiveness of each strategy was as follows: anatomic US, 1.74487 QALYs; ICSI only, 1.74497 QALYs; and all IVF, 1.74499 QALYs. The ICSI-only strategy had an incremental cost-effectiveness ratio (ICER) of $2 840 494 per additional QALY gained when compared to the anatomic-US strategy, and the all-IVF strategy had an ICER of $5 692 457 per additional QALY when compared with the ICSI-only strategy. Both ICERs exceeded considerably the standard willingness-to-pay threshold of $50 000-$100 000 per QALY. In a secondary analysis, the ICSI-only strategy had an ICER of $527 562 per additional case of major CHD detected when compared to the anatomic-US strategy. All IVF had an ICER of $790 510 per case of major CHD detected when compared with ICSI only. It was determined that it would cost society five times more to detect one additional major CHD through intensive screening of all IVF pregnancies than it would cost to pay for the neonate's first year of care. CONCLUSION: The most cost-effective method of screening for CHDs in pregnancies following IVF, either with or without ICSI, is to perform a fetal echo only when abnormal cardiac findings are noted on the detailed anatomy scan. Performing routine fetal echo for all IVF pregnancies is not cost-effective. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Glucocorticoid-induced osteoporosis preventive care in rheumatology patients.

Glucocorticoid-induced osteoporosis (GIOP) is common in patients prescribed with long-term glucocorticoids. Guidelines suggest patients receiving moderate-dose glucocorticoid therapy receive GIOP preventive care. Previous studies have shown preventive care rates are not optimal. We look at GIOP preventive care rates in rheumatology patients and predictors of various components of care. PURPOSE: Glucocorticoid-induced osteoporosis (GIOP) is a common concern in patients prescribed with long-term glucocorticoids. Studies have shown GIOP preventive care is not provided optimally in the general population; however, little is published on GIOP preventive care among patients with rheumatic disease. The objective of this study is to determine the proportion of rheumatology patients who received GIOP preventive care. METHODS: A population-based retrospective quality assurance study of adults seen at the University of Alberta Rheumatology Clinic was performed using the electronic outpatient medical record. Records of adult patients prescribed with prednisone from January 1st to December 31st, 2016 by a rheumatologist were initially included for review. Those who had been prescribed ≥ 7.5 mg/day for ≥ 3 months were assessed for concurrent GIOP preventive care. RESULTS: A total of 745 discreet courses of prednisone were prescribed in 433 patients with 113 meeting the above inclusion criteria. Following the prednisone prescription, 79% were taking vitamin D, 86% were taking calcium, and 50% were prescribed with osteoporosis pharmacotherapy. Twenty-five percent of patients had DXA imaging ordered by the rheumatologist within the first 6 months; of these, 86% of patients completed the DXA. CONCLUSIONS: Overall, our study shows that patients under the care of rheumatologists receive better GIOP preventative care than previously reported care in the general population. However, there is still room for improvement. In particular, men, younger patients, and rural patients seem to be at the most at risk of not receiving optimal GIOP prevention.

Use of prophylactic antibiotics in women with previable prelabor rupture of membranes.

OBJECTIVE: To measure the effect of prophylactic antibiotics given at time of previable prelabor rupture of membranes (PROM) on latency. METHODS: Single center, retrospective cohort study of singleton pregnancies with previable (<23 0/7weeks) PROM. Antibiotics were given at clinician discretion. The primary outcome was latency, defined as duration of time between previable PROM and delivery. Secondary outcomes included delivery at ≥ 23weeks, infant survival, and maternal morbidity. Bivariate analysis compared maternal covariates between women who did and did not receive antibiotics. Antibiotic effect on latency was modeled using a Cox proportional hazards ratio. RESULTS: 213 women with previable PROM were identified; 77 (36%) remained pregnant and thus were included in this analysis. Forty (52%) of 77 received antibiotics. Compared to women who did not receive antibiotics, those who did had PROM at a later median (IQR) estimated gestational age, EGA, (22.2weeks [20.7, 22.5] vs. 19.3weeks [18, 20.7], p < 0.01). Median (IQR) latency was not different between women who did and did not receive antibiotics (2.2 [0.7, 3.9] vs. 1.5 [0.5, 4.6] weeks, p = 0.49). More infants survived to discharge among women who received antibiotics compared to those who did not [17(43%) vs. 3(8%), p < 0.01]. When adjusted for EGA at PROM, antibiotics were associated with longer latency (HR 0.57 [95% CI 0.33, 0.97], p = 0.01). Antibiotic use was not associated with differences in maternal morbidity. CONCLUSION: After adjusting for EGA at PROM, antibiotic receipt was associated with longer latency. Larger prospective studies are needed to define the utility of prophylactic antibiotics in previable PROM.

POST-BIONIAN DEVELOPMENTS IN PSYCHOANALYTIC FIELD THEORY: THE CONTRIBUTIONS OF ANTONINO FERRO AND GIUSEPPE CIVITARESE.

The Bi-Personal Field: Experiences in Child Psychoanalysis. By Antonino Ferro. New York: Routledge, 1992 (1999). 232 pp. The Intimate Room: Theory and Technique of the Analytic Field. By Giuseppe Civitarese. New York: Routledge, 2008 (2010). 240 pp. The Necessary Dream: New Theories and Techniques of Interpretation in Psychoanalysis. By Giuseppe Civitarese; translated by Ian Harvey. London: Karnac, 2013 (2014). 246 pp. The Analytic Field and Its Transformations. By Antonino Ferro and Giuseppe Civitarese. London: Karnac, 2015. 224 pp.

Reversible light-dependent molecular switches on Ag/AgCl nanostructures.

Nanostructured Ag/AgCl substrates were used to generate reversible and highly efficient light-dependent chemical switches based on adsorbed 4,4'-dimercaptoazobenzene (DMAB). DMAB was formed in situ via laser-induced dimerization either from 4-nitrothiophenol (4-NTP) or 4-aminothiophenol (4-ATP). The subsequent reaction pathways of DMAB, however, were quite different as monitored by surface enhanced Raman spectroscopy. In the 4-NTP/DMAB system, AgCl catalyses the reversal of the dimerization. Conversely, irradiation of adsorbed 4-ATP first generated cis-DMAB attached to the surface via two Ag-S bonds, followed by AgCl-catalysed cleavage of one Ag-S bond and cis → trans photoisomerisation of DMAB. In the dark, the trans-isomer thermally reverts to cis-DMAB. The here presented light-dark chemical switches, which work without changing other parameters (e.g., pH, anaerobic vs. aerobic), are based on the (photo)catalytic properties of the Ag/AgCl substrate and do not function on pure metal surfaces.

Mechanisms of post-radiation injury: cerebral microinfarction not a significant factor.

Post-radiation leukoencephalopathy is characterized by cognitive impairment and white matter alternations on imaging. Cerebral small vessel disease (SVD) is one of several suggested etiologies. Cerebral microinfarction (CMI) is a recently described marker of SVD. We sought to examine the rate of CMI as a biomarker of ongoing ischemia among patients who underwent brain radiotherapy (RT). 110 patients treated with RT for primary or metastatic brain tumors were enrolled. A total of 685 brain MRI tests performed 1-108 months post-radiation were examined. The annual incidence of CMI was calculated. Only 2 definite CMI were found (2/685, 0.3 %). The calculated annual incidence of CMI was 0.11. This incidence is similar to the normal population, and lower than the reported incidence in patients with intracerebral hemorrhage or cognitive impairment. CMI incidence in patients treated with brain RT is similar to the general population. This finding suggests that post-radiation leukoencephalopathy and cognitive impairment are not due to active SVD solely but rather secondary to other causes such as inflammation, metabolic or direct cell damage.

Combinatorial immunotherapy for melanoma.

Melanoma has been a long-standing focal point for immunotherapy development. In this review, we explore the evolution of melanoma treatments with particular attention to the history and recent advances in melanoma immunotherapy. We also discuss novel combinations of these modalities and their potential to offer novel therapeutic options for patients with advanced melanoma.

Immunosuppression in liver tumors: opening the portal to effective immunotherapy.

We have recently witnessed substantial progress with immunotherapy for selected diseases. Checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cells are among the most promising agents. Whereas much of the early success with CAR-T cells has been demonstrated with hematological malignancies, important barriers remain for the application of CAR-T cell therapies for the management of metastatic solid tumors. The challenges are particularly apparent when considering primary and metastatic tumors in the liver. At baseline, the intrahepatic space is immunosuppressive and this feature is exploited by malignant cells. Fortunately, our evolving understanding of liver immune cell biology is allowing the development of novel immunotherapeutic strategies for the treatment of liver tumors. Furthermore, the unique anatomic features of the liver make possible highly selective immunotherapeutic delivery approaches that may maximize antitumor efficacy while limiting off-target damage to healthy tissues. This review summarizes the immunobiology of the intrahepatic space and how this knowledge enables identification of hurdles and potential solutions to the barriers facing immunotherapy for liver tumors.

Beyond DNA: An Integrated and Functional Approach for Classifying Germline Variants in Breast Cancer Genes.

Genetic testing for hereditary breast cancer is an integral part of individualized care in the new era of precision medicine. The accuracy of an assay is reliant on not only the technology and bioinformatics analysis utilized but also the experience and infrastructure required to correctly classify genetic variants as disease-causing. Interpreting the clinical significance of germline variants identified by hereditary cancer testing is complex and has a significant impact on the management of patients who are at increased cancer risk. In this review we give an overview of our clinical laboratory's integrated approach to variant assessment. We discuss some of the nuances that should be considered in the assessment of genomic variants. In addition, we highlight lines of evidence such as functional assays and structural analysis that can be useful in the assessment of rare and complex variants.

Calculation of the axion mass based on high-temperature lattice quantum chromodynamics.

Unlike the electroweak sector of the standard model of particle physics, quantum chromodynamics (QCD) is surprisingly symmetric under time reversal. As there is no obvious reason for QCD being so symmetric, this phenomenon poses a theoretical problem, often referred to as the strong CP problem. The most attractive solution for this requires the existence of a new particle, the axion-a promising dark-matter candidate. Here we determine the axion mass using lattice QCD, assuming that these particles are the dominant component of dark matter. The key quantities of the calculation are the equation of state of the Universe and the temperature dependence of the topological susceptibility of QCD, a quantity that is notoriously difficult to calculate, especially in the most relevant high-temperature region (up to several gigaelectronvolts). But by splitting the vacuum into different sectors and re-defining the fermionic determinants, its controlled calculation becomes feasible. Thus, our twofold prediction helps most cosmological calculations to describe the evolution of the early Universe by using the equation of state, and may be decisive for guiding experiments looking for dark-matter axions. In the next couple of years, it should be possible to confirm or rule out post-inflation axions experimentally, depending on whether the axion mass is found to be as predicted here. Alternatively, in a pre-inflation scenario, our calculation determines the universal axionic angle that corresponds to the initial condition of our Universe.

Whole-Organism Cellular Pathology: A Systems Approach to Phenomics.

Phenotype is defined as the state of an organism resulting from interactions between genes, environment, disease, molecular mechanisms, and chance. The purpose of the emerging field of phenomics is to systematically determine and measure phenotypes across biology for the sake of understanding. Phenotypes can affect more than one cell type and life stage, so ideal phenotyping would include the state of every cell type within the context of both tissue architecture and the whole organism at each life stage. In medicine, high-resolution anatomic assessment of phenotype is obtained from histology. Histology's interpretative power, codified by Virchow as cellular pathology, is derived from its ability to discern diagnostic and characteristic cellular changes in diseased tissues. Cellular pathology is observed in every major human disease and relies on the ability of histology to detect cellular change in any cell type due to unbiased pan-cellular staining, even in optically opaque tissues. Our laboratory has shown that histology is far more sensitive than stereomicroscopy for detecting phenotypes in zebrafish mutants. Those studies have also shown that more complete sampling, greater consistency in sample orientation, and the inclusion of phenotypes extending over longer length scales would provide greater coverage of common phenotypes. We are developing technical approaches to achieve an ideal detection of cellular pathology using an improved form of X-ray microtomography that retains the strengths and addresses the weaknesses of histology as a screening tool. We are using zebrafish as a vertebrate model based on the overlaps between zebrafish and mammalian tissue architecture, and a body size small enough to allow whole-organism, volumetric imaging at cellular resolution. Automation of whole-organism phenotyping would greatly increase the value of phenomics. Potential societal benefits would include reduction in the cost of drug development, a reduction in the incidence of unexpected severe drug and environmental toxicity, and more rapid elucidation of the contributions of genes and the environment to phenotypes, including the validation of candidate disease alleles identified in population and personal genetics.

The impact of age on nodal metastases and survival in gastric cancer.

BACKGROUND: In gastric adenocarcinoma, the disparity in lymph node involvement between different age groups has not been thoroughly investigated. The objective of our study was to compare age-associated differences in adequate lymph node harvest and nodal involvement in gastric adenocarcinoma patients. METHODS: We analyzed data extracted from the Surveillance, Epidemiology and End Results database on 13,165 patients diagnosed with stage I-III gastric adenocarcinoma between 2004 and 2011. All patients underwent surgical resection. Statistical comparisons between various age groups were done using the chi-square test and Cox regression. RESULTS: Among 13,165 gastrectomy patients, proportion of patients that had >15 lymph nodes examined decreases significantly with increasing age (P < 0.0001). When adequately staged, older patients had a significantly lower proportion of node-positive tumors (P < 0.0001). Adequate nodal staging was also associated with improved 5-y disease-specific survival across all age groups. CONCLUSIONS: In gastric adenocarcinoma, older patients are less likely to be adequately staged. However, when adequately staged, they are less likely to have node-positive tumors. Adherence to national guidelines, regardless of age, is associated with improved survival outcomes and may alter multimodality management of gastric cancer in the elderly.