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In community settings, negative symptoms and cognitive deficits are the primary barriers to independent living, stable relationships, and employment for individuals suffering from schizophrenia-spectrum disorders. In contrast, however, positive psychotic symptoms (e.g., command hallucinations and persecutory delusions) often drive behavior which serves as the gateway to arrest and criminalization. Historically, the keystone of treatment for positive psychotic symptoms has been antagonism of dopamine D2 receptors in the mesolimbic tract. In this article, we review and explore the principles underlying dopamine antagonism for the treatment of psychosis; optimization of dopamine antagonists in treating positive psychotic symptoms; the advantages of depot dopamine antagonist antipsychotics in forensic settings; the concepts of pharmacokinetic and pharmacodynamic treatment failures; and the role of medication plasma concentrations in optimizing and managing treatment.
Major depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.
1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.
At week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.
Combinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.
Funding Acknowledgements: This study was supported by Assurex Health, Inc.
Prenatal adversity shapes child neurodevelopment and risk for later mental health problems. The quality of the early care environment can buffer some of the negative effects of prenatal adversity on child development. Retrospective studies, in adult samples, highlight epigenetic modifications as sentinel markers of the quality of the early care environment; however, comparable data from pediatric cohorts are lacking. Participants were drawn from the Maternal Adversity Vulnerability and Neurodevelopment (MAVAN) study, a longitudinal cohort with measures of infant attachment, infant development, and child mental health. Children provided buccal epithelial samples (mean age = 6.99, SD = 1.33 years, n = 226), which were used for analyses of genome-wide DNA methylation and genetic variation. We used a series of linear models to describe the association between infant attachment and (a) measures of child outcome and (b) DNA methylation across the genome. Paired genetic data was used to determine the genetic contribution to DNA methylation at attachment-associated sites. Infant attachment style was associated with infant cognitive development (Mental Development Index) and behavior (Behavior Rating Scale) assessed with the Bayley Scales of Infant Development at 36 months. Infant attachment style moderated the effects of prenatal adversity on Behavior Rating Scale scores at 36 months. Infant attachment was also significantly associated with a principal component that accounted for 11.9% of the variation in genome-wide DNA methylation. These effects were most apparent when comparing children with a secure versus a disorganized attachment style and most pronounced in females. The availability of paired genetic data revealed that DNA methylation at approximately half of all infant attachment-associated sites was best explained by considering both infant attachment and child genetic variation. This study provides further evidence that infant attachment can buffer some of the negative effects of early adversity on measures of infant behavior. We also highlight the interplay between infant attachment and child genotype in shaping variation in DNA methylation. Such findings provide preliminary evidence for a molecular signature of infant attachment and may help inform attachment-focused early intervention programs.
Temperature-dependent (173–373 K) hyperpolarized 129Xe nuclear magnetic resonance (129Xe NMR) analyses along with transmission electron microscopy and N2 adsorption measurements have been applied to understand pore structure and interconnectivity of bare and grafted mesoporous silicon sponge (MSS) materials. The Xe NMR chemical shift data indicate the existence of micropores inside the larger mesopore channels and the effects of grafting on the pore surfaces. The grafted layer estimated at 2 nm in thickness blocks the micropores on the surfaces of mesoporous channels. Partitioning of Xe between the micropores and the mesopores in the MSS materials is temperature-dependent, with Xe principally occupying the micropores at lower temperatures. In addition, the temperature-dependent Xe peak shift of MSS materials verifies the increased uniformity and interconnectivity of mesopores after surface grafting. The results from this study provide useful information for design and development of novel materials.
OBJECTIVES/SPECIFIC AIMS: The purpose of the present secondary data analysis was to examine the effect of moderate-severe disturbed sleep before the start of radiation therapy (RT) on subsequent RT-induced pain. METHODS/STUDY POPULATION: Analyses were performed on 676 RT-naïve breast cancer patients (mean age 58, 100% female) scheduled to receive RT from a previously completed nationwide, multicenter, phase II randomized controlled trial examining the efficacy of oral curcumin on radiation dermatitis severity. The trial was conducted at 21 community oncology practices throughout the US affiliated with the University of Rochester Cancer Center NCI’s Community Oncology Research Program (URCC NCORP) Research Base. Sleep disturbance was assessed using a single item question from the modified MD Anderson Symptom Inventory (SI) on a 0–10 scale, with higher scores indicating greater sleep disturbance. Total subjective pain as well as the subdomains of pain (sensory, affective, and perceived) were assessed by the short-form McGill Pain Questionnaire. Pain at treatment site (pain-Tx) was also assessed using a single item question from the SI. These assessments were included for pre-RT (baseline) and post-RT. For the present analyses, patients were dichotomized into 2 groups: those who had moderate-severe disturbed sleep at baseline (score≥4 on the SI; n=101) Versus those who had mild or no disturbed sleep (control group; score=0–3 on the SI; n=575). RESULTS/ANTICIPATED RESULTS: Prior to the start of RT, breast cancer patients with moderate-severe disturbed sleep at baseline were younger, less likely to have had lumpectomy or partial mastectomy while more likely to have had total mastectomy and chemotherapy, more likely to be on sleep, anti-anxiety/depression, and prescription pain medications, and more likely to suffer from depression or anxiety disorder than the control group (all p’s≤0.02). Spearman rank correlations showed that changes in sleep disturbance from baseline to post-RT were significantly correlated with concurrent changes in total pain (r=0.38; p<0.001), sensory pain (r=0.35; p<0.001), affective pain (r=0.21; p<0.001), perceived pain intensity (r=0.37; p<0.001), and pain-Tx (r=0.35; p<0.001). In total, 92% of patients with moderate-severe disturbed sleep at baseline reported post-RT total pain compared with 79% of patients in the control group (p=0.006). Generalized linear estimating equations, after controlling for baseline pain and other covariates (baseline fatigue and distress, age, sleep medications, anti-anxiety/depression medications, prescription pain medications, and depression or anxiety disorder), showed that patients with moderate-severe disturbed sleep at baseline had significantly higher mean values of post-RT total pain (by 39%; p=0.033), post-RT sensory pain (by 41%; p=0.046), and post-RT affective pain (by 55%; p=0.035) than the control group. Perceived pain intensity (p=0.066) and pain-Tx (p=0.086) at post-RT were not significantly different between the 2 groups. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings suggest that moderate-severe disturbed sleep prior to RT is an important predictor for worsening of pain at post-RT in breast cancer patients. There could be several plausible reasons for this. Sleep disturbance, such as sleep loss and sleep continuity disturbance, could result in impaired sleep related recovery and repair of tissue damage associated with cancer and its treatment; thus, resulting in the amplification of pain. Sleep disturbance may also reduce pain tolerance threshold through increased sensitization of the central nervous system. In addition, pain and sleep disturbance may share common neuroimmunological pathways. Sleep disturbance may modulate inflammation, which in turn may contribute to increased pain. Further research is needed to confirm these findings and whether interventions targeting sleep disturbance in early phase could be potential alternate approaches to reduce pain after RT.
Northern China has been identified as an independent centre of domestication for various types of millet and other plant species, but tracing the earliest evidence for the exploitation of wild cereals and thus the actual domestication process has proven challenging. Evidence from microscopic analyses of stone tools, including use-wear, starch and phytolith analyses, however, show that in the Shizitan region of north China, various plants have been exploited as far back as 28000 years ago, and wild millets have been harvested and processed by the time of the Last Glacial Maximum, 24000 years ago. This is some 18000–14000 years before the earliest evidence for domesticated millet in this region.
We present the first data release of the SkyMapper Southern Survey, a hemispheric survey carried out with the SkyMapper Telescope at Siding Spring Observatory in Australia. Here, we present the survey strategy, data processing, catalogue construction, and database schema. The first data release dataset includes over 66 000 images from the Shallow Survey component, covering an area of 17 200 deg2 in all six SkyMapper passbands uvgriz, while the full area covered by any passband exceeds 20 000 deg2. The catalogues contain over 285 million unique astrophysical objects, complete to roughly 18 mag in all bands. We compare our griz point-source photometry with Pan-STARRS1 first data release and note an RMS scatter of 2%. The internal reproducibility of SkyMapper photometry is on the order of 1%. Astrometric precision is better than 0.2 arcsec based on comparison with Gaia first data release. We describe the end-user database, through which data are presented to the world community, and provide some illustrative science queries.
The aim of this analysis was to test if changes in insomnia symptoms and global sleep quality are associated with coinciding changes in depressed mood among older adults. We report on results yielded from secondary analysis of longitudinal data from a clinical trial of older adults (N = 49) aged 55 to 80 years who reported at least moderate levels of sleep problems. All measures were collected at baseline and after the trial ten weeks later. We computed change scores for two separate measures of disturbed sleep, the Athens Insomnia Scale (AIS) and the Pittsburgh Sleep Quality Index (PSQI), and tested their association with change in depressed mood (Beck Depression Inventory-II; BDI-II) in two separate linear regression models adjusted for biological covariates related to sleep (sex, age, body mass index, and NF-κB as a biological marker previously correlated with insomnia and depression). Change in AIS scores was associated with change in BDI-II scores (β = 0.38, p < 0.01). Change in PSQI scores was not significantly associated with change in BDI-II scores (β = 0.17, p = 0.26). Our findings suggest that improvements over ten weeks in insomnia symptoms rather than global sleep quality coincide with improvement in depressed mood among older adults.
Mesoporous silicon sponge (MSS) is considered as a promising anode material for lithium ion batteries because of its preformed meso/macro porous structures that can accommodate large volume expansion during the lithiation process and its superior electrochemical performance. Temperature dependent hyperpolarized (HP) 129Xe NMR was applied to characterize the structure and porosity of MSS materials with varying pores and particle sizes. Our results reveal irregular pore structures with the presence of micropores inside the larger meso/macropore channels and each MSS material has its own characteristic pore environment with a varying degree of nonuniformity and connectivity of pores. This study demonstrates that HP 129Xe NMR is a potentially useful tool for providing a fingerprint of the structure and connectivity of the pores for each material, complementary to other characterization techniques.
The aim of the study was to evaluate the trends in respiratory syncytial virus-related hospitalisations and associated outcomes in children with haemodynamically significant heart disease in the United States of America.
The Kids’ Inpatient Databases (1997–2012) were used to estimate the incidence of respiratory syncytial virus hospitalisation among children ⩽24 months with or without haemodynamically significant heart disease. Weighted multivariable logistic regression and chi-square tests were used to evaluate the trends over time and factors associated with hospitalisation, comparing eras before and after publication of the 2003 American Academy of Pediatrics palivizumab immunoprophylaxis guidelines. Secondary outcomes included in-hospital mortality, morbidity, length of stay, and cost.
Overall, 549,265 respiratory syncytial virus-related hospitalisations were evaluated, including 2518 (0.5%) in children with haemodynamically significant heart disease. The incidence of respiratory syncytial virus hospitalisation in children with haemodynamically significant heart disease decreased by 36% when comparing pre- and post-palivizumab guideline eras versus an 8% decline in children without haemodynamically significant heart disease (p<0.001). Children with haemodynamically significant heart disease had higher rates of respiratory syncytial virus-associated mortality (4.9 versus 0.1%, p<0.001) and morbidity (31.5 versus 3.5%, p<0.001) and longer hospital length of stay (17.9 versus 3.9 days, p<0.001) compared with children without haemodynamically significant heart disease. The mean cost of respiratory syncytial virus hospitalisation in 2009 was $58,166 (95% CI:$46,017, $70,315).
These data provide stakeholders with a means to evaluate the cost–utility of various immunoprophylaxis strategies.
The subsurface exploration of other planetary bodies can be used to unravel their geological history and assess their habitability. On Mars in particular, present-day habitable conditions may be restricted to the subsurface. Using a deep subsurface mine, we carried out a program of extraterrestrial analog research – MINe Analog Research (MINAR). MINAR aims to carry out the scientific study of the deep subsurface and test instrumentation designed for planetary surface exploration by investigating deep subsurface geology, whilst establishing the potential this technology has to be transferred into the mining industry. An integrated multi-instrument suite was used to investigate samples of representative evaporite minerals from a subsurface Permian evaporite sequence, in particular to assess mineral and elemental variations which provide small-scale regions of enhanced habitability. The instruments used were the Panoramic Camera emulator, Close-Up Imager, Raman spectrometer, Small Planetary Linear Impulse Tool, Ultrasonic drill and handheld X-ray diffraction (XRD). We present science results from the analog research and show that these instruments can be used to investigate in situ the geological context and mineralogical variations of a deep subsurface environment, and thus habitability, from millimetre to metre scales. We also show that these instruments are complementary. For example, the identification of primary evaporite minerals such as NaCl and KCl, which are difficult to detect by portable Raman spectrometers, can be accomplished with XRD. By contrast, Raman is highly effective at locating and detecting mineral inclusions in primary evaporite minerals. MINAR demonstrates the effective use of a deep subsurface environment for planetary instrument development, understanding the habitability of extreme deep subsurface environments on Earth and other planetary bodies, and advancing the use of space technology in economic mining.
Recent molecular phylogenetic and molecular clock data both suggest a pre-Mesozoic age for the divergence of the angiosperm lineage from other seed plants, greatly predating the confirmed fossil record of the angiosperm crown group. In addition, molecular phylogenetic studies have not supported the morphologically based conclusion that gnetophytes are the extant sister group to angiosperms. We examine these relationships and divergence ages by using a novel approach of examining the presence of oleanane. This includes the development of methods using zeolites to preferentially reduce hopanes that can co-elute with oleanane. The presence of this molecular fossil strongly correlates with angiosperm diversification; in its functionalized form, along with its triterpenoid precursors, it is found in many living angiosperms. Our data show that among non-angiosperm seed plants examined thus far, oleanane is found only in fossil Cretaceous Bennettitales and Permian Gigantopteridales, both of which share characteristics with angiosperms. Previous morphological phylogenetic results indicate Bennettitales could be a sister group to or member of the angiosperm stem lineage, and results of our preliminary phylogenetic analysis including the Gigantopteridales suggests the same. Our data, based on a new pyrolysis method to treat living species, support previous research indicating that oleanane and its precursors are absent in living gnetophytes. If oleanane originated once in seed plants then the angiosperm stem lineage would have diverged from other seed plant lineages by the late Paleozoic.
To determine the effect of graft choice (allograft, bone-patellar tendon-bone autograft, or hamstring autograft) on deep tissue infections following anterior cruciate ligament (ACL) reconstructions.
Retrospective cohort study.
SETTING AND POPULATION
Patients from 6 US health plans who underwent ACL reconstruction from January 1, 2000, through December 31, 2008.
We identified ACL reconstructions and potential postoperative infections using claims data. A hierarchical stratified sampling strategy was used to identify patients for medical record review to confirm ACL reconstructions and to determine allograft vs autograft tissue implanted, clinical characteristics, and infection status. We estimated infection rates overall and by graft type. We used logistic regression to assess the association between infections and patients’ demographic characteristics, comorbidities, and choice of graft.
On review of 1,452 medical records, we found 55 deep wound infections. With correction for sampling weights, infection rates varied by graft type: 0.5% (95% CI, 0.3%-0.8%) with allografts, 0.6% (0.1%–1.5%) with bone-patellar tendon-bone autografts, and 2.5% (1.9%–3.1%) with hamstring autograft. After adjusting for potential confounders, we found an increased infection risk with hamstring autografts compared with allografts (odds ratio, 5.9; 95% CI, 2.8–12.8). However, there was no difference in infection risk among bone-patellar tendon-bone autografts vs allografts (odds ratio, 1.2; 95% CI, 0.3–4.8).
The overall risk for deep wound infections following ACL reconstruction is low but it does vary by graft type. Infection risk was highest in hamstring autograft recipients compared with allograft recipients and bone-patellar tendon-bone autograft recipients.
Imbalances in dietary fat intakes are linked to several chronic diseases. This study describes dietary intakes and food sources of fat and fatty acids in 1051 Irish adults (aged 18–90 years), using data from the 2011 national food consumption survey, the National Adult Nutrition Survey. It also compares current intakes for 18–64-year-olds with those reported in the last such survey in 2001, the North/South Ireland Food Consumption Survey. Dietary fat intakes were estimated using data from 4-d semi-weighed (2011) and 7-d estimated (2001) food diaries. In 2011, intakes for 18–64-year-olds were as follows: total fat, 34·1 (sd 6·1) % total energy (%TE); SFA, 13·3 (sd 3·3) %TE; MUFA, 12·5 (sd 2·6) %TE; PUFA, 6·1 (sd 2·2) %TE; and trans-fat, 0·511 (sd 0·282) %TE. Apart from MUFA, intakes decreased (P<0·001) compared with 2001. There was no statistically significant difference in intakes of EPA and DHA by 18–64-year-olds in 2011 (269·0 (sd 515·0) mg/d) and 2001 (279·1 (sd 497·5) mg/d). In 2011, adults aged >65 years had the highest intakes of SFA; however, intakes were typically higher than UK-recommended values for all groups. In contrast, intakes of long-chain n-3 fatty acids were lowest in younger age groups. Intakes of trans-fat were well within UK-recommended levels. Although there have been some improvements in the profile of intakes since 2001, imbalances persist in the quantity and quality of dietary fat consumed by Irish adults, most notably for total and SFA and for younger age groups for long-chain n-3 fatty acids.
We report experiments and molecular dynamics calculations on the kinetics of electrodeposited lithium dendrites relaxation as a function of temperature and time. We found that the experimental average length of dendrite population decays via stretched exponential functions of time toward limiting values that depend inversely on temperature. The experimental activation energy derived from initial rates as Ea∼ 6-7 kcal/mole, which is closely matched by MD calculations, based on the ReaxFF force field for metallic lithium. Simulations reveal that relaxation proceeds in several steps via increasingly larger activation barriers. Incomplete relaxation at lower temperatures is therefore interpreted a manifestation of cooperative atomic motions into discrete topologies that frustrate monotonic progress by ‘caging’.
In this work, the structure and conductive structure of perfluorinated sulfonated ionomers were investigated by tapping mode, material sensitive atomic force microscopy (AFM). At cross section of membranes, large ordered lamellar-like areas were found. From adhesion force mappings, approximately 50 nm large water-rich areas could be identified by their low adhesion. These areas were interpreted as ionically conductive phase. They appeared circular and isolated before any forced current flow through the sample (activation). After activation, branched, long and flat ionically conductive phase structures in direction of applied voltage were found. They were interpreted as the formation of a continuous ionically conducting network formed by the current flow. In a second part, the material sensitive imaging was used to analyze the distribution of ionomer and platinum covered carbon particles in fuel cell electrodes. The analysis was based on the high adhesion of ionomers compared to the carbon supported catalyst particles.
Phase maps of Co–Cr alloys bonded to dental porcelain cycled through an incremental number of porcelain firings at two separate thicknesses (0.5 and 1 mm) were analyzed. Bulk hexagonal close-packed (hcp) phase vol% of the alloy was found to increase with the number of porcelain firings for both 0.5 and 1 mm specimens. At the metal-porcelain interface, a uniform fine-grained hcp phase was observed. The depth and grain size of this hcp layer increased with the number of porcelain firings with the thicker specimens undergoing more substantial growth and transformation. Simple heat transfer modeling of the specimens during heat treatment cycles indicated that the thicker specimen had more time at high temperature to affect the face-centered cubic to hcp phase transformation. Therefore, the amount of porcelain firings and the thickness of the alloy should be considered and kept to a minimal when manufacturing metal-porcelain restoration.
Children's observed effortful control (EC) at 30, 42, and 54 months (n = 145) was predicted from the interaction between mothers' observed parenting with their 30-month-olds and three variants of the solute carrier family C6, member 3 (SLC6A3) dopamine transporter gene (single nucleotide polymorphisms in intron8 and intron13, and a 40 base pair variable number tandem repeat [VNTR] in the 3′-untranslated region [UTR]), as well as haplotypes of these variants. Significant moderating effects were found. Children without the intron8-A/intron13-G, intron8-A/3′-UTR VNTR-10, or intron13-G/3′-UTR VNTR-10 haplotypes (i.e., haplotypes associated with the reduced SLC6A3 gene expression and thus lower dopamine functioning) appeared to demonstrate altered levels of EC as a function of maternal parenting quality, whereas children with these haplotypes demonstrated a similar EC level regardless of the parenting quality. Children with these haplotypes demonstrated a trade-off, such that they showed higher EC, relative to their counterparts without these haplotypes, when exposed to less supportive maternal parenting. The findings revealed a diathesis–stress pattern and suggested that different SLC6A3 haplotypes, but not single variants, might represent different levels of young children's sensitivity/responsivity to early parenting.