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The spread of the Zika virus (ZIKV) in the Americas led to large outbreaks across the region and most of the Southern hemisphere. Of greatest concern were complications following acute infection during pregnancy. At the beginning of the outbreak, the risk to unborn babies and their clinical presentation was unclear. This report describes the methods and results of the UK surveillance response to assess the risk of ZIKV to children born to returning travellers. Established surveillance systems operating within the UK – the paediatric and obstetric surveillance units for rare diseases, and national laboratory monitoring – enabled rapid assessment of this emerging public health threat. A combined total of 11 women experiencing adverse pregnancy outcomes after possible ZIKV exposure were reported by the three surveillance systems; five miscarriages, two intrauterine deaths and four children with clinical presentations potentially associated with ZIKV infection. Sixteen women were diagnosed with ZIKV during pregnancy in the UK. Amongst the offspring of these women, there was unequivocal laboratory evidence of infection in only one child. In the UK, the number and risk of congenital ZIKV infection for travellers returning from ZIKV-affected countries is very small.
Background:ATP8A2 mutations have only recently been associated with human disease. We present the clinical features from the largest cohort of patients with this disorder reported to date. Methods: An observational study of 9 unreported and 2 previously reported patients with biallelic ATP8A2 mutations was carried out at multiple centres. Results: The mean age of the cohort was 9.4 years old (range: 2.5-28 yrs). All patients demonstrated developmental delay, severe hypotonia and movement disorders: chorea/choreoathetosis (100%), dystonia (27%) or facial dyskinesia (18%). Hypotonia was apparent at birth (70%) or before 6 months old (100%). Optic atrophy was observed in 75% of patients who had a funduscopic examination. MRI of the brain was normal for most patients with a small proportion showing mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Epilepsy was seen in two older patients. Conclusions:ATP8A2 gene mutations have emerged as a cause of a novel phenotype characterized by developmental delay, severe hypotonia and hyperkinetic movement disorders. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation. Early recognition of the cardinal features of this condition will facilitate diagnosis of this disorder.
A considerable body of evidence suggests that early caregiving may affect the short-term functioning and longer term development of the hypothalamic–pituitary–adrenocortical axis. Despite this, most research to date has been cross-sectional in nature or restricted to relatively short-term longitudinal follow-ups. More important, there is a paucity of research on the role of caregiving in low- and middle-income countries, where the protective effects of high-quality care in buffering the child's developing stress regulation systems may be crucial. In this paper, we report findings from a longitudinal study (N = 232) conducted in an impoverished periurban settlement in Cape Town, South Africa. We measured caregiving sensitivity and security of attachment in infancy and followed children up at age 13 years, when we conducted assessments of hypothalamus–pituitary–adrenocortical axis reactivity, as indexed by salivary cortisol during the Trier Social Stress Test. The findings indicated that insecure attachment was predictive of reduced cortisol responses to social stress, particularly in boys, and that attachment status moderated the impact of contextual adversity on stress responses: secure children in highly adverse circumstances did not show the blunted cortisol response shown by their insecure counterparts. Some evidence was found that sensitivity of care in infancy was also associated with cortisol reactivity, but in this case, insensitivity was associated with heightened cortisol reactivity, and only for girls. The discussion focuses on the potentially important role of caregiving in the long-term calibration of the stress system and the need to better understand the social and biological mechanisms shaping the stress response across development in low- and middle-income countries.
Developmental psychopathologists face the difficult task of identifying the environmental conditions that may contribute to early childhood behavior problems. Highly stressed caregivers can exacerbate behavior problems, while children with behavior problems may make parenting more difficult and increase caregiver stress. Unknown is: (a) how these transactions originate, (b) whether they persist over time to contribute to the development of problem behavior and (c) what role resilience factors, such as child executive functioning, may play in mitigating the development of problem behavior. In the present study, transactional relations between caregiving stress, executive functioning, and behavior problems were examined in a sample of 1,388 children with prenatal drug exposures at three developmental time points: early childhood (birth to age 5), middle childhood (ages 6 to 9), and early adolescence (ages 10 to 13). Transactional relations differed between caregiving stress and internalizing versus externalizing behavior. Targeting executive functioning in evidence-based interventions for children with prenatal substance exposure who present with internalizing problems and treating caregiving psychopathology, depression, and parenting stress in early childhood may be particularly important for children presenting with internalizing behavior.
Ethnohistorical and ethnographic observations from around the world indicate that projectiles were often made differently for warfare and hunting. Using experiential archaeology and analysis of a thousand years’ worth of data from the middle Gila River in Arizona, the authors argue that side notched arrow points were produced for hunting large animals and were designed to be retrieved and reused, while unnotched points were intended for single use and for another purpose: to kill people. The data suggests furthermore that the region witnessed a steady increase in levels of violence during the period under study.
To examine inappropriate antibiotic prescribing for acute respiratory tract infections (RTIs) in ambulatory care to help target antimicrobial stewardship interventions.
Design and Setting
Retrospective analysis of RTI visits within general internal medicine (GIM) and family medicine (FM) ambulatory practices at an inner-city academic medical center from 2008 to 2010.
Patient, physician, and practice characteristics were analyzed using multivariable logistic regression to determine factors predictive of inappropriate prescribing; physicians in the highest and lowest antibiotic-prescribing quartiles were compared using χ2 analysis.
Visits with FM providers, female gender, and self-reported race/ethnicity as white or Hispanic were significantly associated with inappropriate antibiotic prescribing. Physicians in the lowest quartile prescribed antibiotics for 5%–28% (mean, 21%) of RTI visits; physicians in the highest quartile prescribed antibiotics for 54%–85% (mean, 65%) of RTI visits. High prescribers had fewer African-American patients and more patients who were younger and privately insured. High prescribers had more patients with chronic lung disease. A GIM practice pod with a low prescriber was 3.0 times more likely to have a second low prescriber than other practice pods, whereas pods with a high prescriber were 1.3 times more likely to have a second high prescriber.
Medical specialty was the only physician factor predictive of inappropriate prescribing when patient gender, race, and comorbidities were taken into account. Possible disparities in care need further study. Stewardship education in medical school, enlisting low prescribers as physician leaders, and targeting interventions to the highest prescribers might be more effective approaches to antimicrobial stewardship.
The Helicon-Cathode(HelCat) device is a medium-size linear experiment suitable for a wide range of basic plasma science experiments in areas such as electrostatic turbulence and transport, magnetic relaxation, and high power microwave (HPM)-plasma interactions. The HelCat device is based on dual plasma sources located at opposite ends of the 4 m long vacuum chamber – an RF helicon source at one end and a thermionic cathode at the other. Thirteen coils provide an axial magnetic field B ⩾ 0.220 T that can be configured individually to give various magnetic configurations (e.g. solenoid, mirror, cusp). Additional plasma sources, such as a compact coaxial plasma gun, are also utilized in some experiments, and can be located either along the chamber for perpendicular (to the background magnetic field) plasma injection, or at one of the ends for parallel injection. Using the multiple plasma sources, a wide range of plasma parameters can be obtained. Here, the HelCat device is described in detail and some examples of results from previous and ongoing experiments are given. Additionally, examples of planned experiments and device modifications are also discussed.
Integrative, multilevel approaches investigating neurobiological systems relevant to threat detection promise to advance understanding of the pathophysiology of major depressive disorder (MDD). In this study we considered key neuronal and hormonal systems in adolescents with MDD and healthy controls (HC). The goals of this study were to identify group differences and to examine the association of neuronal and hormonal systems. MDD and HC adolescents (N = 79) aged 12–19 years were enrolled. Key brain measures included amygdala volume and amygdala activation to an emotion face-viewing task. Key hormone measures included cortisol levels during a social stress task and during the brain scan. MDD and HC adolescents showed group differences on amygdala functioning and patterns of cortisol levels. Amygdala activation in response to emotional stimuli was positively associated with cortisol responses. In addition, amygdala volume was correlated with cortisol responses, but the pattern differed in depressed versus healthy adolescents, most notably for unmedicated MDD adolescents. The findings highlight the value of using multilevel assessment strategies to enhance understanding of pathophysiology of adolescent MDD, particularly regarding how closely related biological threat systems function together while undergoing significant developmental shifts.
Specific roles of individual CDPKs vary, but in general they mediate essential biological functions necessary for parasite survival. A comparative analysis of the structure-activity relationships (SAR) of Neospora caninum, Eimeria tenella and Babesia bovis calcium-dependent protein kinases (CDPKs) together with those of Plasmodium falciparum, Cryptosporidium parvum and Toxoplasma gondii was performed by screening against 333 bumped kinase inhibitors (BKIs). Structural modelling and experimental data revealed that residues other than the gatekeeper influence compound–protein interactions resulting in distinct sensitivity profiles. We subsequently defined potential amino-acid structural influences within the ATP-binding cavity for each orthologue necessary for consideration in the development of broad-spectrum apicomplexan CDPK inhibitors. Although the BKI library was developed for specific inhibition of glycine gatekeeper CDPKs combined with low inhibition of threonine gatekeeper human SRC kinase, some library compounds exhibit activity against serine- or threonine-containing CDPKs. Divergent BKI sensitivity of CDPK homologues could be explained on the basis of differences in the size and orientation of the hydrophobic pocket and specific variation at other amino-acid positions within the ATP-binding cavity. In particular, BbCDPK4 and PfCDPK1 are sensitive to a larger fraction of compounds than EtCDPK1 despite the presence of a threonine gatekeeper in all three CDPKs.
Prior studies assessing the metabolic effects of different types of carbohydrates have focused on their glycaemic response. However, the response of postprandial cardiometabolic risk indicators has not been considered in these studies. The present study assessed postprandial lipid responses to two forms of carbohydrates used as reference foods for glycaemic index determinations, white bread (50 g available carbohydrate) and glucose (50 g), under controlled conditions and with intra-individual replicate determinations. A total of twenty adults (20–70 years) underwent two cycles of challenges with each pair of reference foods (four challenges/person), administered in a random order on separate days under standard conditions. Serum lipids (total cholesterol, LDL-cholesterol, HDL-cholesterol, TAG and NEFA), glucose and insulin were monitored for 5 h post-ingestion. Oral glucose resulted in greater glycaemic and insulinaemic responses than white bread for the first 90 min and a greater subsequent decline after 120 min (P =0·0001). The initial decline in serum NEFA concentrations was greater after the oral glucose than after the white bread challenge, as was the rebound after 150 min (P =0·001). Nevertheless, the type of carbohydrate had no significant effect on postprandial total cholesterol, LDL-cholesterol and HDL-cholesterol concentrations. Following an initial modest rise in TAG concentrations in response to both challenges, the values dropped below the fasting values for oral glucose but not for the white bread challenge. These data suggest that the type of carbohydrate used to determine the glycaemic index, bread or glucose, has little or modest effects on postprandial plasma cholesterol concentrations. Differences in TAG and NEFA concentrations over the 5 h time period were modest, and their clinical relevance is unclear.
Significant new opportunities for astrophysics and cosmology have been identified at low radio frequencies. The Murchison Widefield Array is the first telescope in the southern hemisphere designed specifically to explore the low-frequency astronomical sky between 80 and 300 MHz with arcminute angular resolution and high survey efficiency. The telescope will enable new advances along four key science themes, including searching for redshifted 21-cm emission from the EoR in the early Universe; Galactic and extragalactic all-sky southern hemisphere surveys; time-domain astrophysics; and solar, heliospheric, and ionospheric science and space weather. The Murchison Widefield Array is located in Western Australia at the site of the planned Square Kilometre Array (SKA) low-band telescope and is the only low-frequency SKA precursor facility. In this paper, we review the performance properties of the Murchison Widefield Array and describe its primary scientific objectives.
Quercetin, a flavonol in fruits and vegetables, has been demonstrated to have antioxidant, anti-inflammatory and immunomodulating influences. The purpose of the present study was to determine if quercetin, vitamin C and niacin supplements (Q-500 = 500 mg/d of quercetin, 125 mg/d of vitamin C and 5 mg/d of niacin; Q-1000 = 1000 mg/d of quercetin, 250 mg/d of vitamin C and 10 mg/d of niacin) would alter small-molecule metabolite profiles and serum quercetin conjugate levels in adults. Healthy adults (fifty-eight women and forty-two men; aged 40–83 years) were assigned using a randomised double-blinded placebo-controlled trial to one of three supplement groups (Q-1000, Q-500 or placebo). Overnight fasted blood samples were collected at 0, 1 and 3 months. Quercetin conjugate concentrations were measured using ultra-performance liquid chromatography (UPLC)-MS/MS, and metabolite profiles were measured using two MS platforms (UPLC-quadrupole time-of-flight MS (TOFMS) and GC-TOFMS). Statistical procedures included partial least square discriminant analysis (PLS-DA) and linear mixed model analysis with repeated measures. After accounting for age, sex and BMI, quercetin supplementation was associated with significant shifts in 163 metabolites/quercetin conjugates (false discovery rate, P< 0·05). The top five metabolite shifts were an increase in serum guaiacol, 2-oxo-4-methylthiobutanoic acid, allocystathionine and two bile acids. Inflammatory and oxidative stress metabolites were not affected. PLS-DA revealed a clear separation only between the 1000 mg/d and placebo groups (Q2Y= 0·763). The quercetin conjugate, isorhamnetin-3-glucuronide, had the highest concentration at 3 months followed by quercetin-3-glucuronide, quercetin-3-sulphate and quercetin diglucuronide. In human subjects, long-term quercetin supplementation exerts disparate and wide-ranging metabolic effects and changes in quercetin conjugate concentrations. Metabolic shifts were apparent at the 1000 mg/d dose; further research is required to understand the health implications of these shifts.
Energy is essential for human development and energy systems are a crucial entry point for addressing the most pressing global challenges of the 21st century, including sustainable economic and social development, poverty eradication, adequate food production and food security, health for all, climate protection, conservation of ecosystems, peace and security. Yet, more than a decade into the 21st century, current energy systems do not meet these challenges.
A major transformation is therefore required to address these challenges and to avoid potentially catastrophic future consequences for human and planetary systems. The Global Energy Assessment (GEA) demonstrates that energy system change is the key for addressing and resolving these challenges. The GEA identifies strategies that could help resolve the multiple challenges simultaneously and bring multiple benefits. Their successful implementation requires determined, sustained and immediate action.
Transformative change in the energy system may not be internally generated; due to institutional inertia, incumbency and lack of capacity and agility of existing organizations to respond effectively to changing conditions. In such situations clear and consistent external policy signals may be required to initiate and sustain the transformative change needed to meet the sustainability challenges of the 21st century.
The industrial revolution catapulted humanity onto an explosive development path, whereby, reliance on muscle power and traditional biomass was replaced mostly by fossil fuels. In 2005, some 78% of global energy was based on fossil energy sources that provided abundant and ever cheaper energy services to more than half the people in the world.
Energy is essential for human development and energy systems are a crucial entry point for addressing the most pressing global challenges of the 21st century, including sustainable economic, and social development, poverty eradication, adequate food production and food security, health for all, climate protection, conservation of ecosystems, peace, and security. Yet, more than a decade into the 21st century, current energy systems do not meet these challenges.
In this context, two considerations are important. The first is the capacity and agility of the players within the energy system to seize opportunities in response to these challenges. The second is the response capacity of the energy system itself, as the investments are long-term and tend to follow standard financial patterns, mainly avoiding risks and price instabilities. This traditional approach does not embrace the transformation needed to respond properly to the economic, environmental, and social sustainability challenges of the 21st century.
A major transformation is required to address these challenges and to avoid potentially catastrophic consequences for human and planetary systems. The GEA identifies strategies that could help resolve the multiple challenges simultaneously and bring multiple benefits. Their successful implementation requires determined, sustained, and immediate action.
The industrial revolution catapulted humanity onto an explosive development path, whereby reliance on muscle power and traditional biomass was replaced mostly by fossil fuels. In 2005, approximately 78% of global energy was based on fossil energy sources that provided abundant and ever cheaper energy services to more than half the world's population.