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Glucose intolerance during pregnancy – a major driver of gestational diabetes mellitus (GDM) – has significant short and long-term health consequences for both the mother and child. As GDM prevalence continues to escalate, there is growing need for preventative strategies. There is limited but suggestive evidence that myo-inositol (MI) and probiotics (PB) could improve glucose tolerance during pregnancy. This study tested the hypothesis that MI and/or PB supplementation would reduce the risk of glucose intolerance during pregnancy. Female C57BL/6 mice were randomised to receive either no treatment, MI, PB (Lactobacillusrhamnosus and Bifidobacteriumlactis), or both (MIPB) for five weeks. They were then provided with high fat diet (HFD) for one week before mating commenced and throughout mating/gestation, while remaining on their respective treatments. An oral glucose tolerance test occurred at gestational day (GD) 16.5 and tissue collection at GD18.5. Neither MI or PB, separately or combined, improved glucose tolerance. However, MI and PB both independently increased adipose tissue expression of Ir, Irs1, Akt2, and Pck1, and PB also increased Pparγ. MI was associated with reduced gestational weight gain, whilst PB was associated with increased maternal fasting glucose, total cholesterol and pancreas weight. These results suggest that MI and PB may improve insulin intracellular signalling in adipose tissue but this did not translate to meaningful differences in glucose tolerance. The absence of fasting hyperglycaemia or insulin resistance suggests this is a very mild model of GDM, which may have affected our ability to assess the impact of these nutrients.
Stress can exert modulatory effects on pain perception in animals, as exposure to a stressor can result in either the reduction or amplification of the perceived severity of pain. These phenomena are widely described as stress-induced analgesia (SIA) and stress-induced hyperalgesia (SIH). The two are mediated by the same underlying mechanisms, but occur due to different stressors and different responses from the pain pathway. SIA and SIH have been demonstrated with a variety of stress and pain stimuli in rodents, humans and other mammals. There is some evidence that SIA occurs in birds and that they have the neurological systems and brain regions necessary for SIH. Tonic immobility (TI) is related to SIA in mammals, and there is evidence the avian brain is compatible with TI having analgesic effect, but it could have a hyperalgesic effect. This review looks at the mechanisms and evidence of SIA, SIH and TI in mammals and discusses evidence relating to the occurrence of these phenomena in birds.
The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
To make a case for greater American involvement in Africa is to take cognizance of what has gone before — eclectic embrace followed by selective disengagement. The Nixon Administration has opted for a policy of designating certain target countries for bilateral assistance and political cultivation. The itineraries of American public figures from the Vice President and Secretary of State to the astronauts and Mrs. Nixon tell us where the emphases are being placed: on the two long-standing areas of concern, Liberia and Ethiopia; on Africa's most populous state, Nigeria; on one of its larger states, Zaire, and on the home of one of Africa's senior pragmatic statesmen, Kenya. Somewhat more peripheral interest is maintained in Ghana, which has moved into the column of “reasonable” regimes. Most recently the situation in Sudan has dazzled U.S. policymakers with visions of picking up chips from the Soviets and conjuring up the type of Cold War determinant of involvement popular in the 1960s.
Through autonomic and affective mechanisms, adverse childhood experiences (ACEs) may disrupt the capacity to regulate negative emotions, increasing craving and exacerbating risk for opioid use disorder (OUD) among individuals with chronic pain who are receiving long-term opioid analgesic pharmacotherapy. This study examined associations between ACEs, heart rate variability (HRV) during emotion regulation, and negative emotional cue-elicited craving among a sample of female opioid-treated chronic pain patients at risk for OUD. A sample of women (N = 36, mean age = 51.2 ± 9.5) with chronic pain receiving long-term opioid analgesic pharmacotherapy (mean morphine equivalent daily dose = 87.1 ± 106.9 mg) were recruited from primary care and pain clinics to complete a randomized task in which they viewed and reappraised negative affective stimuli while HRV and craving were assessed. Both ACEs and duration of opioid use significantly predicted blunted HRV during negative emotion regulation and increased negative emotional cue-elicited craving. Analysis of study findings from a multiple-levels-of-analysis approach suggest that exposure to childhood abuse occasions later emotion dysregulation and appetitive responding toward opioids in negative affective contexts among adult women with chronic pain, and thus this vulnerable clinical population should be assessed for OUD risk when initiating a course of extended, high-dose opioids for pain management.
The effect of small noise in a smooth dynamical system is negligible on any finite time interval; in this paper we study situations where the effect persists on intervals increasing to ∞. Such an asymptotic regime occurs when the system starts from an initial condition that is sufficiently close to an unstable fixed point. In this case, under appropriate scaling, the trajectory converges to a solution of the unperturbed system started from a certain random initial condition. In this paper we consider the case of one-dimensional diffusions on the positive half-line; this case often arises as a scaling limit in population dynamics.
Dementia is a leading cause of morbidity and mortality without pharmacologic prevention or cure. Mounting evidence suggests that adherence to a Mediterranean dietary pattern may slow cognitive decline, and is important to characterise in at-risk cohorts. Thus, we determined the reliability and validity of the Mediterranean Diet and Culinary Index (MediCul), a new tool, among community-dwelling individuals with mild cognitive impairment (MCI). A total of sixty-eight participants (66 % female) aged 75·9 (sd 6·6) years, from the Study of Mental and Resistance Training study MCI cohort, completed the fifty-item MediCul at two time points, followed by a 3-d food record (FR). MediCul test–retest reliability was assessed using intra-class correlation coefficients (ICC), Bland–Altman plots and κ agreement within seventeen dietary element categories. Validity was assessed against the FR using the Bland–Altman method and nutrient trends across MediCul score tertiles. The mean MediCul score was 54·6/100·0, with few participants reaching thresholds for key Mediterranean foods. MediCul had very good test–retest reliability (ICC=0·93, 95 % CI 0·884, 0·954, P<0·0001) with fair-to-almost-perfect agreement for classifying elements within the same category. Validity was moderate with no systematic bias between methods of measurement, according to the regression coefficient (y=−2·30+0·17x) (95 % CI −0·027, 0·358; P=0·091). MediCul over-estimated the mean FR score by 6 %, with limits of agreement being under- and over-estimated by 11 and 23 %, respectively. Nutrient trends were significantly associated with increased MediCul scoring, consistent with a Mediterranean pattern. MediCul provides reliable and moderately valid information about Mediterranean diet adherence among older individuals with MCI, with potential application in future studies assessing relationships between diet and cognitive function.
Inequalities in infant mortality rates (IMRs) are rising in some low- and middle-income countries (LMICs) and decreasing in others, but the explanation for these divergent trends is unclear. We investigate whether government expenditures and redistribution are associated with reductions in inequalities in IMRs. We estimated country-level fixed-effects panel regressions for 48 LMICs (142 country observations). Slope and Relative Indices of Inequality in IMRs (SII and RII) were calculated from Demographic and Health Surveys between 1993 and 2013. RII and SII were regressed on government expenditure (total, health and non-health) and redistribution, controlling for gross domestic product (GDP), private health expenditures, a democracy indicator, country fixed effects and time. Mean SII and RII was 39.12 and 0.69, respectively. In multivariate models, a 1 percentage point increase in total government expenditure (% of GDP) was associated with a decrease in SII of −2.468 [95% confidence intervals (CIs): −4.190, −0.746] and RII of −0.026 (95% CIs: −0.048, −0.004). Lower inequalities were associated with higher non-health government expenditure, but not higher government health expenditure. Associations with inequalities were non-significant for GDP, government redistribution, and private health expenditure. Understanding how non-health government expenditure reduces inequalities in IMR, and why health expenditures may not, will accelerate progress towards the Sustainable Development Goals.
Background: To develop a scale to quantify and discriminate orthostatic from non-orthostatic symptoms. We present initial validation and reliability of orthostatic and non-orthostatic symptom scores taken from the Orthostatic Discriminate and Severity Scale (ODSS). Methods: Validity and reliability were assessed in participants with and without orthostatic intolerance. Convergent validity was assessed by correlating symptoms scores with previously validated tools (Autonomic Symptom Profile (ASP) and the Orthostatic Hypotension Questionnaire (OHQ)). Clinical validity was assessed by correlating scores against standardized autonomic testing. Test-retest reliability was calculated using an intra-class correlation coefficient. Results:Convergent Validity: Orthostatic (OS) and Non-Orthostatic (NS) Symptom Scores from 77 controls and 67 patients with orthostatic intolerance were highly correlated with both the Orthostatic Intolerance index of the ASP (OS:r=0.903;NS:r=0.651; p<0.001) and the OHQ: (OS:r=0.800;NS:r=0.574; p<0.001). Clinical Validity: Symptom Scores were significantly correlated with the blood pressure change during head-up tilt (OS:r=-0.445;NS:r=-0.354; p<0.001). Patients with orthostatic intolerance had significantly higher symptom scores compared to controls (OS:66.5±18.1 vs. 17.4±12.9; NS:19.9±11.3 vs. 10.2±6.8; p<0.001, respectively). Test-retest reliability: Both symptom scores were highly reliable (OS:r=0.956;NS:r=0.574, respectively; p<0.001) with an internal consistency of 0.978 and 0.729, respectively. Conclusions: Our initial results demonstrate that the ODSS is capable of producing valid and reliable Orthostatic and Non-Orthostatic Symptom Scores.
Background: Neurogenic orthostatic hypotension (NOH), defined as a drop in systolic blood pressure (SBP) ≥30mmHg on standing or head-up tilt, is associated with autonomic dysfunction. The cortical autonomic network (CAN) is a network of brain regions associated with autonomic function. Our aim was to investigate CAN activation patterns in NOH patients during autonomic testing. Methods: Fifteen controls (61±14 years) and 13 NOH patients (68±6 years;p=0.1) completed: 1)Deep Breathing (DB), 2)Valsalva maneuver (VM) and 3)Lower-body negative pressure (LBNP) during a functional MRI. Blood-oxygen level dependent (BOLD) contrasts were obtained and contrasted. Results: Compared to controls (C), patients (NOH) had significantly smaller heart rate (HR) responses to DB (C:15.3±9.6 vs.NOH:6.0±2.2) and VR’s (C:2.1±0.47 vs.NOH:1.2±0.1;p<0.001). Patients had larger SBP drops during LBNP (C: -22.3±6 vs.NOH: -61±22) with -significantly smaller compensatory tachycardias (19±8.5 vs.7.6±4.3)(p<0.001). BOLD response: During VM, controls had greater activation in the right (R) hippocampus (T-value:7.34), left (L) posterior cingulate (T-value:7.22) bilateral mid-cingulate (TR-value:5.76; TL-value:6.84) and bilateral thalamus (TR-value:7.23, TL-value:8.16)(pFWE<0.001). Following subtraction analysis, brain activation patterns showed no significant differences in the regions of interest in response to DB and LBNP. Conclusions: During tests of autonomic function, NOH patient had different cortical activation patterns during VM only. Cortical activation pattern during DB and LBNP showed similar patterns to that of controls.
The efficiency of grass nitrogen utilisation for milk production tends to be low, due partly to the slow rate of release of energy in the rumen which reduces the efficiency of capture of rapidly degradable plant proteins by the rumen microbial population. When additional sugars are infused into the rumen, microbial protein production is increased (Rooke et al., 1987). The objective of this study was to assess milk production using a grass variety that has been bred to express elevated water soluble carbohydrate (WSC) concentrations.
Eight multiparous Holstein-Friesian dairy cows in mid lactation (176 days ± s.e. 3.6) were used in a continuous design, zero-grazing experiment. Following covariate measurements taken from all animals on a standard grazing diet, four animals were each offered one of two varieties of perennial ryegrass at ad libitum rate: AberDove, bred to express high WSC concentrations; and AberElan, a commercially available variety, used as a control.
Central nervous system infections (CNSI) are a leading cause of death and long-term disability in children. Using ICD-10 data from 2005 to 2015 from three central hospitals in Ho Chi Minh City (HCMC), Vietnam, we exploited generalized additive mixed models (GAMM) to examine the spatial-temporal distribution and spatial and climatic risk factors of paediatric CNSI, excluding tuberculous meningitis, in this setting. From 2005 to 2015, there were 9469 cases of paediatric CNSI; 33% were ⩽1 year old at admission and were mainly diagnosed with presumed bacterial CNSI (BI) (79%), the remainder were >1 year old and mainly diagnosed with presumed non-bacterial CNSI (non-BI) (59%). The urban districts of HCMC in proximity to the hospitals as well as some outer districts had the highest incidences of BI and non-BI; BI incidence was higher in the dry season. Monthly BI incidence exhibited a significant decreasing trend over the study. Both BI and non-BI were significantly associated with lags in monthly average temperature, rainfall, and river water level. Our findings add new insights into this important group of infections in Vietnam, and highlight where resources for the prevention and control of paediatric CNSI should be allocated.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
We aimed to describe the natural history of heavy episodic drinking (HED) and associated harms from adolescence to young adulthood in a large Australian population cohort study.
The Australian Temperament Project consists of mothers and babies (4–8 months) recruited from Infant Welfare Centres and followed every 2 to 4 years until age 28 years. Analyses were based on data from 1156 young people (497 male; 659 female) surveyed repeatedly at ages 16, 18, 20, 24 and 28 years. We used dual processes latent class growth analysis to estimate trajectories of HED and associated harms, employing a piecewise approach to model the hypothesized rise and subsequent fall across adolescence and the late twenties, respectively.
We identified four sex-specific trajectories and observed little evidence of maturing-out across the twenties. In males, a normative pattern of increasing HED across the twenties with little related harm was observed (40% of the male sample). Early and late starter groups that peaked in harms at age 20 years with only minor attenuation in binging thereafter were also observed (6.1% and 35%, respectively). In females, a normative pattern of increasing, but moderate, HED with little related harm was observed (44% of the female sample). Early and late starter groups were also identified (18% and 17%, respectively); however, unlike males, the female late starter group showed a pattern of increasing HED and related harms.
Continued patterns of risky alcohol use and related harms are apparent for both males and females across the twenties.
Dislocation/grain-boundary (GB) interactions have been studied in situ in polycrystalline ice using synchrotron X-ray topography in the temperature range 0° to –15°C GBs were observed to act both as sources of lattice dislocations and as strong obstacles to dislocation motion. Dislocations were observed to form pile-ups at GBs upon loading. Generally the basal slip system with the highest Schmid factor was found to be the most active, and dislocations were emitted from GB facets as semi-hexagonal loops in order to relieve the stress build-up from GB sliding. When the relative orientation of two adjacent grains and the orientation of the GB between them with respect to the loading direction discouraged GB sliding, thus suppressing dislocation nucleation at the GB, dislocations originating in one grain piled up at the GB and led to slip transmission through the GB The latter geometrical arrangement is rarely encountered, suggesting that slip transmission through grain boundaries in ice is a rare event. When basal slip was suppressed, i.e. when the loading direction lay in the basal plane, slip occurred by the glide of a fast edge segment on non-basal planes.
While glacier fabric reflects the accumulated strain, detailed azimuthal information is required to link the microstructure to the flow, and this is not easily gathered at depth. Borehole logging provides a way to obtain a log of azimuthal orientation of tilted stratigraphic features that can be used to orient the core with respect to glacier flow. We demonstrate this using acoustic borehole logs and the ice core from a 162 m borehole in Upper Fremont Glacier, Wind River Range, Wyoming, USA. We measured the dip of tilted dust and bubble layers in the actual ice core, identified them on the borehole log, then used their strike to orient the core sections containing them. We examined the crystal orientation fabric of our samples, using electron backscatter diffraction in a scanning electron microscope. When we compared the orientation of the tilted layers in some samples with the fabric, we found that the normal to the foliation and the c-axes maxima both pointed in the direction of maximum shear stress. This illustrates the usefulness of borehole logs for orienting ice cores after removal from the borehole, and for developing a better understanding of fabric development.
OBJECTIVES/SPECIFIC AIMS: The off-target and organ-specific toxicities observed in cancer immunotherapy present an obstacle to T-cell-based therapeutics. A recent clinical trial underscored the need for improved methods to define TCR specificity after melanoma patients treated with TCR engineered T-cells suffered from fatal cardiovascular toxicity arising from the unpredicted recognition of a muscle-specific peptide. METHODS/STUDY POPULATION: To address this drawback to T-cell-based immunotherapies, we developed a novel protein engineering approach to define the peptide specificity of a given TCR. Here, directed evolution in a yeast display system produced a large scale peptide library, where recognition by the melanoma reactive DMF5 TCR acted as the guiding selective pressure. After this technique identified a panel of putative cross reactive peptides, sequence analysis and computational modeling followed by kinetic binding experiments and structural analysis determined the DMF5 TCR recognizes 2 distinct classes of peptides through chemically distinct mechanisms. RESULTS/ANTICIPATED RESULTS: This information led to the rational, structure-based design of additional cross reactive peptides and introduced a unique approach to screen the human proteome and identify the TCR targets which triggered undesired autoimmunity when this molecule was used in clinical trials. DISCUSSION/SIGNIFICANCE OF IMPACT: The distinct chemical nature of the 2 peptide classes suggest TCRs are more cross reactive than previously thought, presenting an obstacle to cell-based immunotherapy. Defining the peptide specificity of TCRs is of high interest to the immunology community, and will lead to improved approaches to designing engineered TCRs for cell therapy.
Background: Standardized data collection for traumatic brain injury (TBI) (including concussion) using common data elements (CDEs) has strengthened clinical care and research capacity in the United States and Europe. Currently, Ontario healthcare providers do not collect uniform data on adult patients diagnosed with concussion. Objective: The Ontario Concussion Care Strategy (OCCS) is a collaborative network of multidisciplinary healthcare providers, brain injury advocacy groups, patient representatives, and researchers with a shared vision to improve concussion care across the province, starting with the collection of standardized data. Methods: The International Framework of Functioning Disability and Health was selected as the conceptual framework to inform the selection of CDEs. The CDEs recommended by the OCCS were identified using key literature, including the National Institute of Neurological Disorders and Stroke–Zurich Consensus Statements for concussion in sport and the Ontario Neurotrauma Foundation Concussion/mTBI clinical guidelines. Results: The OCCS has recommended and piloted CDEs for Ontario that are readily available at no cost, clinically relevant, patient friendly, easy to interpret, and recognized by the international scientific community. Conclusions: The implementation of CDEs can help to shift Ontario toward internationally recognized standard data collection, and in so doing yield a more comprehensive evidence-based approach to care while also supporting rigorous research.
Households with pets are considered a high-risk population, presenting many challenges to response and recovery efforts. Research indicates that households with pets are less likely to evacuate during disasters, and pets left behind pose a health risk to relief workers and the general public. This pilot study explores a brief education intervention targeting households with pets as a method of increasing general household preparedness, with the purpose of facilitating evacuation and protective behaviors in this population.
A convenience sample of households with pets was recruited to participate in a one-group pre- and post-survey design evaluating the impact of a brief education intervention on increasing pet-specific and general household preparedness levels.
Results suggest that the sample population was below national estimates in basic household preparedness before the intervention. Post-survey results indicate an increase in completion of some preparedness tasks after the intervention. There was a statistically significant increase in overall pet preparedness at the P=0.10 level; however, that difference did not translate into general household preparedness.
The findings from this study are consistent with those from previous literature suggesting that persons often place the needs of their pets above their own; however, the use of a brief education intervention may be successful in increasing pet-specific preparedness levels, which may be useful in successful evacuation and pet well-being. (Disaster Med Public Health Preparedness. 2018;12:441–445)