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Mixed presentations, defined by simultaneous occurrence of depressive and manic symptoms, are difficult to treat. Antidepressants, although commonly used, have weak evidence of efficacy and may increase risk of mood destabilization. The aim of this pooled post hoc analysis was to evaluate the efficacy of cariprazine in the treatment of bipolar depression with or without concurrent manic symptoms.
Patients from 3 randomized, double-blind, placebo-controlled studies who met DSM-IV-TR or DSM-5 criteria for bipolar I disorder with a current major depressive episode were identified to have concurrent manic symptoms by baseline Young Mania Rating Scale total score ≥4. Efficacy was assessed in cariprazine 1.5 and 3 mg/day dose groups versus placebo; analyses included the least squares mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score.
Of 1383 patients randomized to treatment, 808 (58.4%) had concurrent manic symptoms. For patients with manic symptoms, mean reduction in MADRS total score from baseline to week 6 was significantly greater for both cariprazine 1.5 and 3 mg/day compared with placebo, with least squares mean differences (LSMDs) versus placebo of −2.5 (p = .0033) and −2.9 (p = .0010), respectively; for patients without manic symptoms, the LSMD was significant for 1.5 mg/day (−3.3; p = .0008), but not for 3 mg/day (−1.9; p = .0562).
The results of this post hoc analysis suggest that cariprazine may be an appropriate treatment option for patients with bipolar I depression with or without manic symptoms, with higher doses potentially more effective in patients with manic symptoms.
A new fossil site in a previously unexplored part of western Madagascar (the Beanka Protected Area) has yielded remains of many recently extinct vertebrates, including giant lemurs (Babakotia radofilai, Palaeopropithecus kelyus, Pachylemur sp., and Archaeolemur edwardsi), carnivores (Cryptoprocta spelea), the aardvark-like Plesiorycteropus sp., and giant ground cuckoos (Coua). Many of these represent considerable range extensions. Extant species that were extirpated from the region (e.g., Prolemur simus) are also present. Calibrated radiocarbon ages for 10 bones from extinct primates span the last three millennia. The largely undisturbed taphonomy of bone deposits supports the interpretation that many specimens fell in from a rock ledge above the entrance. Some primates and other mammals may have been prey items of avian predators, but human predation is also evident. Strontium isotope ratios (87Sr/86Sr) suggest that fossils were local to the area. Pottery sherds and bones of extinct and extant vertebrates with cut and chop marks indicate human activity in previous centuries. Scarcity of charcoal and human artifacts suggests only occasional visitation to the site by humans. The fossil assemblage from this site is unusual in that, while it contains many sloth lemurs, it lacks ratites, hippopotami, and crocodiles typical of nearly all other Holocene subfossil sites on Madagascar.
This paper presents a comprehensive analytical approach to the modelling of wall-pressure fluctuations under a turbulent boundary layer, unifying and expanding the analytical models that have been proposed over many decades. The Poisson equation governing pressure fluctuations is Fourier transformed in the wavenumber domain to obtain a modified Helmholtz equation, which is solved with a Green’s function technique. The source term of the differential equations is composed of turbulence–mean shear and turbulence–turbulence interaction terms, which are modelled separately within the hypothesis of a joint normal probability distribution of the turbulent field. The functional expression of the turbulence statistics is shown to be the most critical point for a correct representation of the wall-pressure spectrum. The effect of various assumptions on the shape of the longitudinal correlation function of turbulence is assessed in the first place with purely analytical considerations using an idealised flow model. Then, the effect of the hypothesis on the spectral distribution of boundary-layer turbulence on the resulting wall-pressure spectrum is compared with the results of direct numerical simulation computations and pressure measurements on a controlled-diffusion aerofoil. The boundary layer developing over the suction side of this aerofoil in test conditions is characterised by an adverse pressure gradient. The final part of the paper discusses the numerical aspect of wall-pressure spectrum computation. A Monte Carlo technique is used for a fast evaluation of the multi-dimensional integral formulation developed in the theoretical part.
The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
Leishmania rely heavily on glycans to complete their digenetic life cycle in both mammalian and phlebotomine sand fly hosts. Leishmania promastigotes secrete a proteophosphoglycan-rich gel (Promastigote Secretory Gel, PSG) that is regurgitated during transmission and can exacerbate infection in the skin. Here we explored the role of PSG from natural Leishmania-sand fly vector combinations by obtaining PSG from Leishmania (L.) major-infected Phlebotomus (P.) papatasi and P. duboscqi and L. tropica-infected P. arabicus. We found that, in addition to the vector's saliva, the PSG from L. major and L. tropica potently exacerbated cutaneous infection in BALB/c mice, improved the probability of developing a patent cutaneous lesion, parasite growth and the evolution of the lesion. Of note, the presence of PSG in the inoculum more than halved the prepatent period of cutaneous L. tropica infection from an average of 32 weeks to 13 weeks. In addition, L. major and L. tropica PSG extracted from the permissive experimental vector, Lutzomyia (Lu.) longipalpis, also exacerbated infections in mice. These results reinforce and extend the hypothesis that PSG is an important and evolutionarily conserved component of Leishmania infection that can be used to facilitate experimental infection for drug and vaccine screening.
In Race and the Making of American Political Science, Jessica Blatt argues that the professionalization of the discipline was deeply entwined with ideas about racial difference, and the concomitant attempt by leading scholars to define and defend a system of racial hierarchy in the United States and beyond. Although it focuses on the period from the late nineteenth century through the 1930s, the book also raises fundamental questions about the historical legacy of racialist arguments for professional political science, the extent of their continuing resonance, and contemporary implications for both academic and broader civic discourse. We have asked a range of leading political scientists to consider and respond to Professor Blatt’s important call for scholarly self-reflexivity.
Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder, manifestations of which range from subtle abnormalities demonstrable only on neuropsychometric testing, such as mild cognitive impairment, psychomotor slowing, and impaired bimanual and visuomotor coordination (referred to as minimal HE or MHE), through to overt manifestations such as disruption of the sleep cycle, disturbed attention span, change in personality, confusion, disorientation, and coma. Aside from the uncommon patient with HE due to a congenital deficiency of an urea cycle enzyme, in whom liver function is otherwise normal, HE occurs as a consequence of severe acute or chronic liver disease or in the setting of porto-systemic venous shunting, the latter arising either spontaneously, usually in the presence of portal venous hypertension complicating cirrhosis, or iatrogenically, following portal venous hypertension-decompressive shunt procedures, both surgical and radiologically placed. Irrespective of the clinical setting in which it arises, the severity of overt HE is traditionally graded using systems such as the West Haven criteria  (Table 30.1).
Fatigue syndromes (FSs) affect large numbers of individuals, yet evidence from epidemiological studies on adverse outcomes, such as premature death, is limited.
Cohort study involving 385 general practices in England that contributed to the Clinical Practice Research Datalink (CPRD) with linked inpatient Hospital Episode Statistics (HES) and Office for National Statistics (ONS) cause of death information. A total of 10 477 patients aged 15 years and above, diagnosed with a FS during 2000–2014, were individually matched with up to 20 comparator patients without a history of having a FS. Prevalence ratios (PRs) were estimated to compare the FS and comparison cohorts on clinical characteristics. Adjusted hazard ratios (HRs) for subsequent adverse outcomes were estimated from stratified Cox regression models.
Among patients diagnosed with FSs, we found elevated baseline prevalence of: any psychiatric illness (PR 1.77; 95% CI 1.72–1.82), anxiety disorders (PR 1.92; 1.85–1.99), depression (PR 1.89; 1.83–1.96), psychotropic prescriptions (PR 1.68; 1.64–1.72) and comorbid physical illness (PR 1.28; 1.23–1.32). We found no significant differences in risks for: all-cause mortality (HR 0.99; 0.91–1.09), natural death (HR 0.99; 0.90–1.09), unnatural death (HR 1.00; 0.59–1.72) or suicide (HR 1.68; 0.78–3.63). We did, however, observe a significantly elevated non-fatal self-harm risk: HR 1.83; 1.56–2.15.
The absence of elevated premature mortality risk is reassuring. The raised prevalence of mental illness and increased non-fatal self-harm risk indicate a need for enhanced assessment and management of psychopathology associated with fatigue syndromes.
Depictions of eye images and messages encouraging compliance with social norms have successfully motivated behavioral change in a variety of experimental and applied settings. We studied the effect of these 2 visual cues on hand hygiene adherence in a cohort of hospital-based healthcare providers participating in an electronic monitoring and feedback program.
Prospective, quasi-experimental study utilizing an interrupted time-series design. Intervention placards depicting an image of eyes, a social norms message, or a control placard were placed near soap and alcohol-based hand-rub dispensers on 2 hospital units. Placards were alternated every 10 days. Hand hygiene opportunities and adherence rates were assessed electronically via the CenTrak Hand Hygiene Compliance Solution.
A total of 166 nurses and certified nursing assistants (74 on a medical-surgical unit and 92 on a progressive care unit) were monitored electronically over the 4-month study period. In total, 184,172 electronic observations were collected (110,903 on a medical-surgical unit and 73,269 on a progressive care unit). The median daily number of electronic observations was 1,471 (interquartile range, 1,337–1,584). The preintervention baseline hand hygiene adherence rate was 70%. No statistically significant increase in hand hygiene adherence was observed as a result of either intervention.
Displaying eye images or a social norms message in the hospital environment did not result in measurable improvements in HH adherence in a cohort of healthcare providers participating in an electronic monitoring and feedback program.
Analysis of milk BHB concentration by Fourier-transform infrared (FTIR) spectrometry more frequently than regular milk testing could help dairy producers in decision making, particularly if it would be possible to use small hand-stripped samples (hereinafter simply called samples) taken between dairy herd improvement (DHI) test-samples analysed using DHI algorithms. The aim of this Research Communication was to evaluate milk BHB concentration and the prevalence of elevated milk BHB concentration analysed by FTIR spectrometry compared with flow-injection analysis (SKALAR) from samples taken at different times relative to the milking. A total of 293 early-lactation cows in 44 commercial dairy herds were involved in the study. Herds were visited once during the morning milking when a routine DHI test-sample was obtained using in-line milk samplers. Additional milk samples were taken by hand stripping as follows: (1) Just before connecting the milking machine; (2) immediately after removing the milking machine; (3) 3 h after milking and (4) 6 h after milking. Milk samples were analysed for BHB concentration by FTIR and SKALAR, the latter being the reference method. Milk BHB concentration from samples taken before milking was different between FTIR and SKALAR whereas no difference was noted for other sampling times, although milk BHB concentration rose as time after milking increased. Except for DHI test-samples for which prevalence was not different between analysis methods, prevalence of elevated milk BHB concentration (≥0.15 mmol/l) was greater for FTIR analysis. However, no difference in prevalence was observed between SKALAR and FTIR when using a threshold of ≥0.20 mmol/l. In summary, hand-stripped milk samples taken any time after removing the milking machine until 6 h after the milking can be recommended for FTIR analysis of elevated milk BHB concentration prevalence provided a threshold of 0.20 mmol/l is used.
CVD and associated metabolic diseases are linked to chronic inflammation, which can be modified by diet. The objective of the present study was to determine whether there is a difference in inflammatory markers, blood metabolic and lipid panels and lymphocyte gene expression in response to a high-fat dairy food challenge with or without milk fat globule membrane (MFGM). Participants consumed a dairy product-based meal containing whipping cream (WC) high in saturated fat with or without the addition of MFGM, following a 12 h fasting blood draw. Inflammatory markers including IL-6 and C-reactive protein, lipid and metabolic panels and lymphocyte gene expression fold changes were measured using multiplex assays, clinical laboratory services and TaqMan real-time RT-PCR, respectively. Fold changes in gene expression were determined using the Pfaffl method. Response variables were converted into incremental AUC, tested for differences, and corrected for multiple comparisons. The postprandial insulin response was significantly lower following the meal containing MFGM (P < 0·01). The gene encoding soluble epoxide hydrolase (EPHX2) was shown to be more up-regulated in the absence of MFGM (P = 0·009). Secondary analyses showed that participants with higher baseline cholesterol:HDL-cholesterol ratio (Chol:HDL) had a greater reduction in gene expression of cluster of differentiation 14 (CD14) and lymphotoxin β receptor (LTBR) with the WC+MFGM meal. The protein and lipid composition of MFGM is thought to be anti-inflammatory. These exploratory analyses suggest that addition of MFGM to a high-saturated fat meal modifies postprandial insulin response and offers a protective role for those individuals with higher baseline Chol:HDL.
I examine the ability of the U.S. investor protection regime to limit insider trading returns, absent Section 16(b) of the Securities Exchange Act of 1934 (the short-swing rule). I find that in this setting, U.S. insiders execute short-swing trades that i) beat the market by approximately 15 basis points per day and ii) systematically divest ahead of disappointing earnings announcements. These results indicate that the bright-line rule restricting short-horizon round-trip insider trading plays a substantial role in protecting outside investors from privately informed insiders in the United States.
This article summarizes the results of controlled experiments in which flaked-stone points that varied in impact strength by a factor of almost three were shot at media that were increasingly inelastic and therefore likely to break the points. Broken tips were reworked if possible, and used again under the same conditions. Our results show that all damage to low impact-strength materials, especially obsidian, was generally catastrophic, and, consequently, these points could only rarely be reworked. The fact that low-strength stones were commonly used to make small arrowpoints suggests that reworking was not a primary concern for their designers. Furthermore, in those instances when broken tips could be reworked, their performance declined. In addition, reworking broken points also resulted in shapes that are uncommon in many arrowpoint assemblages. Our results suggest that the original design attributes of arrowpoints may have been less affected by reworking, and, consequently, may more accurately suggest temporal and behavioral associations.
We aimed to spatially describe mental illness prevalence in England at small-area geographical level, as measured by prevalence of depression, severe mental illness (SMI) and antidepressant prescription volume in primary care records, and how much of their variation was explained by deprivation, social fragmentation and sociodemographic characteristics.
Information on prevalence of depression and SMI was obtained from the Quality and Outcomes Framework (QOF) administrative dataset for 2015/16 and the national dispensing dataset for 2015/16. Linear regression models were fitted to examine ecological associations between deprivation, social fragmentation, other sociodemographic characteristics and mental illness prevalence.
Mental illness prevalence varied within and between regions, with clusters of high prevalence identified across England. Our models explained 33.4–68.2% of variability in prevalence, but substantial variability between regions remained after adjusting for covariates. People in socially cohesive and socially deprived areas were more likely to be diagnosed with depression, while people in more socially fragmented and more socially deprived areas were more likely to be diagnosed with SMI.
Our findings suggest that to tackle mental health inequalities, attention needs to be targeted at more socially deprived localities. The role of social fragmentation warrants further investigation, and it is possible that depression remains undiagnosed in more socially fragmented areas. The wealth of routinely collected data can provide robust evidence to aid optimal resource allocation. If comparable data are available in other countries, similar methods could be deployed to identify high prevalence clusters and target funding to areas of greater need.
To characterize the association of longitudinal changes in maternal anthropometric measures with neonatal anthropometry and to assess to what extent late-gestational changes in maternal anthropometry are associated with neonatal body composition.
In a prospective cohort of pregnant women, maternal anthropometry was measured at six study visits across pregnancy and after birth, neonates were measured and fat and lean mass calculated. We estimated maternal anthropometric trajectories and separately assessed rate of change in the second (15–28 weeks) and third trimester (28–39 weeks) in relation to neonatal anthropometry. We investigated the extent to which tertiles of third-trimester maternal anthropometry change were associated with neonatal outcomes.
Women were recruited from twelve US sites (2009–2013).
Non-obese women with singleton pregnancies (n 2334).
A higher rate of increase in gestational weight gain was associated with larger-birth-weight infants with greater lean and fat mass. In contrast, higher rates of increase in maternal anthropometry measures were not associated with infant birth weight but were associated with decreased neonatal lean mass. In the third trimester, women in the tertile of lowest change in triceps skinfold (−0·57 to −0·06 mm per week) had neonates with 35·8 g more lean mass than neonates of mothers in the middle tertile of rate of change (−0·05 to 0·06 mm per week).
The rate of change in third-trimester maternal anthropometry measures may be related to neonatal lean and fat mass yet have a negligible impact on infant birth weight, indicating that neonatal anthropometry may provide additional information over birth weight alone.
Previous studies of conduct disorder (CD) have reported structural and functional alterations in the limbic system. However, the white matter tracts that connect limbic regions have not been comprehensively studied. The uncinate fasciculus (UF), a tract connecting limbic to prefrontal regions, has been implicated in CD. However, CD-related alterations in other limbic tracts, such as the cingulum and the fornix, have not been investigated. Furthermore, few studies have examined the influence of sex and none have been adequately powered to test whether the relationship between CD and structural connectivity differs by sex. We examined whether adolescent males and females with CD exhibit differences in structural connectivity compared with typically developing controls.
We acquired diffusion-weighted magnetic resonance imaging data from 101 adolescents with CD (52 females) and 99 controls (50 females). Data were processed for deterministic spherical deconvolution tractography. Virtual dissections of the UF, the three subdivisions of the cingulum [retrosplenial cingulum (RSC), parahippocampal and subgenual cingulum], and the fornix were performed and measures of fractional anisotropy (FA) and hindrance-modulated orientational anisotropy (HMOA) were analysed.
The CD group had lower FA and HMOA in the right RSC tract relative to controls. Importantly, these effects were moderated by sex – males with CD significantly lower FA compared to male controls, whereas CD and control females did not differ.
Our results highlight the importance of considering sex when studying the neurobiological basis of CD. Sex differences in RSC connectivity may contribute to sex differences in the clinical presentation of CD.