We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.
To save content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about saving content to .
To save content items to your Kindle, first ensure coreplatform@cambridge.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about saving to your Kindle.
Note you can select to save to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Increasing interest in three-dimensional nanostructures adds impetus to electron microscopy techniques capable of imaging at or below the nanoscale in three dimensions. We present a reconstruction algorithm that takes as input a focal series of four-dimensional scanning transmission electron microscopy (4D-STEM) data. We apply the approach to a lead iridate, Pb$_2$Ir$_2$O$_7$, and yttrium-stabilized zirconia, Y$_{0.095}$Zr$_{0.905}$O$_2$, heterostructure from data acquired with the specimen in a single plan-view orientation, with the epitaxial layers stacked along the beam direction. We demonstrate that Pb–Ir atomic columns are visible in the uppermost layers of the reconstructed volume. We compare this approach to the alternative techniques of depth sectioning using differential phase contrast scanning transmission electron microscopy (DPC-STEM) and multislice ptychographic reconstruction.
A system for examination of the peripheral nerves of the upper limb is described in this chapter. This includes the ulnar, median, radial, axillary and musculocutaneous nerves. The steps are inspection followed by a screen test to decide if the lesion is likely to be radial, median or ulnar. Then the nerve is examined in more detail by testing sensation and movement in relation to that nerve. Provocation tests are performed if necessary. This chapter also describes nerve compression as a result of thoracic outlet syndrome, as this may be a differential diagnosis. In the ‘Advanced corner’ Tinel’s sign and Valleix phenomenon as well as ‘double crush’ are described.
Clozapine is the only drug licensed for treatment-resistant schizophrenia (TRS) but the real-world clinical and cost-effectiveness of community initiation of clozapine is unclear.
Aims
The aim was to assess the feasibility and cost-effectiveness of community initiation of clozapine.
Method
This was a naturalistic study of community patients recommended for clozapine treatment.
Results
Of 158 patients recommended for clozapine treatment, 88 (56%) patients agreed to clozapine initiation and, of these, 58 (66%) were successfully established on clozapine. The success rate for community initiation was 65.4%; which was not significantly different from that for in-patient initiation (58.82%, χ2(1,88) = 0.47, P = 0.49). Following clozapine initiation, there was a significant reduction in median out-patient visits over 1 year (from 24.00 (interquartile range (IQR) = 14.00–41.00) to 13.00 visits (IQR = 5.00–24.00), P < 0.001), and 2 years (from 47.50 visits (IQR = 24.75–71.00) to 22.00 (IQR = 11.00–42.00), P < 0.001), and a 74.71% decrease in psychiatric hospital bed days (z = −2.50, P = 0.01). Service-use costs decreased (1 year: –£963/patient (P < 0.001); 2 years: –£1598.10/patient (P < 0.001). Subanalyses for community-only initiation also showed significant cost reductions (1 year: –£827.40/patient (P < 0.001); 2 year: –£1668.50/patient (P < 0.001) relative to costs prior to starting clozapine. Relative to before initiation, symptom severity was improved in patients taking clozapine at discharge (median Positive and Negative Syndrome Scale total score: initial visit: 80 (IQR = 71.00–104.00); discharge visit 50.5 (IQR = 44.75–75.00), P < 0.001) and at 2 year follow-up (Health of Nation Outcome Scales total score median initial visit: 13.00 (IQR = 9.00–15.00); 2 year follow-up: 8.00 (IQR = 3.00–13.00), P = 0.023).
Conclusions
These findings indicate that community initiation of clozapine is feasible and is associated with significant reductions in costs, service use and symptom severity.
OBJECTIVES/GOALS: We aimed to determine if GLP-1 receptor agonists exert beneficial effects on surrogate measures of cardiovascular function independently of weight loss. Our objective was to compare the outcomes between GLP-1 receptor agonist treatment versus a similar drug without cardiovascular benefit versus weight loss through diet alone. METHODS/STUDY POPULATION: We enrolled 88 individuals with obesity (BMI ≥ 30kg/m2) and pre-diabetes and randomized them in a 2:1:1 ratio to 14 weeks of the GLP-1 receptor agonist liraglutide, the dipeptidyl peptidase-4 inhibitor sitagliptin, or hypocaloric diet. Sitagliptin blocks degradation of endogenous GLP-1 but does not cause weight loss or lower adverse cardiovascular outcomes. Treatment was double-blinded and placebo-controlled for drug, and unblinded for diet. Primary endpoints were flow-mediated dilation (FMD) to assess endothelial vasodilatory function, and plasminogen activator inhibitor-1 (PAI-1) to assess endothelial fibrinolytic function. We used a general linear model for each outcome and included gender as a covariate for FMD. Baseline characteristics were similar. Mean age was 50, with 32% men and 13% black. RESULTS/ANTICIPATED RESULTS: At 14 weeks, diet and liraglutide caused weight loss (diet -4.3 ± 3.2 kg, P<0.01; liraglutide -2.7 ± 3.2, P<0.01), while sitagliptin did not (-0.7 ± 2.0, P=0.17). Diet did not improve FMD at 14 weeks compared to baseline (+0.9%, 95% CI [-1.5, 3.3], P=0.46). FMD tended to increase after liraglutide and sitagliptin but was not significant (liraglutide +1.2 [-0.3, 2.8], P=0.12; sitagliptin +1.6 [-0.6, 3.8], P=0.15). Given that liraglutide and sitagliptin work through the same GLP-1 pathway, we combined the liraglutide and sitagliptin groups for overall effect on FMD, which was significantly improved from baseline (+1.4 [0.1, 2.8], P=0.04). Diet and liraglutide improved PAI-1 at 14 weeks (diet -4.4U/mL, [-8.5, -0.2], P=0.04; liraglutide -3.4 [-6.0, -0.7], P=0.01), while sitagliptin did not (-1.4 [-5.1, 2.3], P=0.46). DISCUSSION/SIGNIFICANCE: Activation of the GLP-1 pathway by liraglutide or sitagliptin improves FMD independent of weight loss, while PAI-1 improvement is weight-loss dependent and is only seen after liraglutide or diet. Our study suggests the cardiovascular benefit of liraglutide may be due to combined improvements in endothelial vasodilatory and fibrinolytic function.
To assess preventability of hospital-onset bacteremia and fungemia (HOB), we developed and evaluated a structured rating guide accounting for intrinsic patient and extrinsic healthcare-related risks.
Design:
HOB preventability rating guide was compared against a reference standard expert panel.
Participants:
A 10-member panel of clinical experts was assembled as the standard of preventability assessment, and 2 physician reviewers applied the rating guide for comparison.
Methods:
The expert panel independently rated 82 hypothetical HOB scenarios using a 6-point Likert scale collapsed into 3 categories: preventable, uncertain, or not preventable. Consensus was defined as concurrence on the same category among ≥70% experts. Scenarios without consensus were deliberated and followed by a second round of rating.
Two reviewers independently applied the rating guide to adjudicate the same 82 scenarios in 2 rounds, with interim revisions. Interrater reliability was evaluated using the κ (kappa) statistic.
Results:
Expert panel consensus criteria were met for 52 scenarios (63%) after 2 rounds.
After 2 rounds, guide-based rating matched expert panel consensus in 40 of 52 (77%) and 39 of 52 (75%) cases for reviewers 1 and 2, respectively. Agreement rates between the 2 reviewers were 84% overall (κ, 0.76; 95% confidence interval [CI], 0.64–0.88]) and 87% (κ, 0.79; 95% CI, 0.65–0.94) for the 52 scenarios with expert consensus.
Conclusions:
Preventability ratings of HOB scenarios by 2 reviewers using a rating guide matched expert consensus in most cases with moderately high interreviewer reliability. Although diversity of expert opinions and uncertainty of preventability merit further exploration, this is a step toward standardized assessment of HOB preventability.
Early in the COVID-19 pandemic, the World Health Organization stressed the importance of daily clinical assessments of infected patients, yet current approaches frequently consider cross-sectional timepoints, cumulative summary measures, or time-to-event analyses. Statistical methods are available that make use of the rich information content of longitudinal assessments. We demonstrate the use of a multistate transition model to assess the dynamic nature of COVID-19-associated critical illness using daily evaluations of COVID-19 patients from 9 academic hospitals. We describe the accessibility and utility of methods that consider the clinical trajectory of critically ill COVID-19 patients.
In this paper, we consider changes to memorial practices for mental health service users during the asylum period of the mid-nineteenth up to the end of the twentieth century and into the twenty-first century. The closing of large asylums in the UK has been largely welcomed by professionals and service-users alike, but their closure has led to a decrease in continuous and consistent care for those with enduring mental health challenges. Temporary and time-limited mental health services, largely dedicated to crisis management and risk reduction have failed to enable memory practices outside the therapy room. This is an unusual case of privatised memories being favoured over collective memorial activity. We argue that the collectivisation of service user memories, especially in institutions containing large numbers of long-stay patients, would benefit both staff and patients. The benefit would be in the development of awareness of how service users make sense of their past in relation to their present stay in hospital, how they might connect with others in similar positions and how they may connect with the world and others upon future release. This seems to us central to a project of recovery and yet is rarely practised in any mental health institution in the UK, despite being central to other forms of care provision, such as elderly and children's care services. We offer some suggestions on how collective models of memory in mental health might assist in this project of recovery and create greater visibility between past, present and future imaginings.
The three-way intersection of gender, relationship-to-care-recipient and care-giving demands has not, to our knowledge, been examined in relation to the wellbeing of family care-givers. We explore inequalities in depressive symptoms and life satisfaction, comparing wives, husbands, daughters and sons providing very-intensive care (36+ hours/week) with those providing less care and disparities between these groups in the factors related to disadvantage. Data from the Canadian Longitudinal Study on Aging (N = 5,994) support the existence of differences between the groups. Very-intensive care-giving wives report the most depressive symptoms and lowest life satisfaction; less-intensive care-giving sons report the fewest depressive symptoms, and less-intensive care-giving daughters report the highest life satisfaction. However, group differences in life satisfaction disappear among very-intensive care-givers. Drawing on Intersectionality and Stress Process theories, data from regression analyses reveal a non-significant gender–relationship–demand interaction term, but, health, socio-economic and social support resources play a strong mediating role between care demand and wellbeing. Analyses of the eight groups separately reveal diversity in the care-giving experience. Among less-intensive care-givers, the mediating role of resources remains strong even as differences are evident. Among very-intensive care-givers, the role of resources is less and differences in wellbeing between the groups are magnified. Policy implications emphasise the imperative to personalise services to meet the varied needs of care-givers.
The coronavirus disease 2019 (COVID-19) pandemic has significantly increased depression rates, particularly in emerging adults. The aim of this study was to examine longitudinal changes in depression risk before and during COVID-19 in a cohort of emerging adults in the U.S. and to determine whether prior drinking or sleep habits could predict the severity of depressive symptoms during the pandemic.
Methods
Participants were 525 emerging adults from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), a five-site community sample including moderate-to-heavy drinkers. Poisson mixed-effect models evaluated changes in the Center for Epidemiological Studies Depression Scale (CES-D-10) from before to during COVID-19, also testing for sex and age interactions. Additional analyses examined whether alcohol use frequency or sleep duration measured in the last pre-COVID assessment predicted pandemic-related increase in depressive symptoms.
Results
The prevalence of risk for clinical depression tripled due to a substantial and sustained increase in depressive symptoms during COVID-19 relative to pre-COVID years. Effects were strongest for younger women. Frequent alcohol use and short sleep duration during the closest pre-COVID visit predicted a greater increase in COVID-19 depressive symptoms.
Conclusions
The sharp increase in depression risk among emerging adults heralds a public health crisis with alarming implications for their social and emotional functioning as this generation matures. In addition to the heightened risk for younger women, the role of alcohol use and sleep behavior should be tracked through preventive care aiming to mitigate this looming mental health crisis.
Background: Medulloblastoma (MB) is the most common solid malignant pediatric brain neoplasm. Group 3 (G3) MB, particularly MYC amplified G3 MB, is the most aggressive subgroup with the highest frequency of children presenting with metastatic disease, and is associated with a poor prognosis. To further our understanding of the role of MSI1 in MYC amplified G3 MB, we performed an unbiased integrative analysis of eCLIP binding sites, with changes observed at the transcriptome, the translatome, and the proteome after shMSI1 inhibition. Methods: Primary human pediatric MBs, SU_MB002 and HD-MB03 were kind gifts from Dr. Yoon-Jae Cho (Harvard, MS) and Dr. Till Milde (Heidelberg) and cultured for in vitro and in vivo experiments. eCLIP, RNA-seq, Polysome-seq, and TMT-MS were completed as previously described. Results:MSI1 is overexpressed in G3 MB. shRNA Msi1 interference resulted in a reduction in tumour burden conferring a survival advantage to mice injected with shMSI1 G3MB cells. Robust ranked multiomic analysis (RRA) identified an unconventional gene set directly perturbed by MSI1 in G3 MB. Conclusions: Our robust unbiased integrative analysis revealed a distinct role for MSI1 in the maintenance of the stem cell state in G3 MB through post-transcriptional modification of multiple pathways including identification of unconventional targets such as HIPK1.
Plasmodium coatneyi has been proposed as an animal model for human Plasmodium falciparum malaria as it appears to replicate many aspects of pathogenesis and clinical symptomology. As part of the ongoing evaluation of the rhesus macaque model of severe malaria, a detailed ultrastructural analysis of the interaction between the parasite and both the host erythrocytes and the microvasculature was undertaken. Tissue (brain, heart and kidney) from splenectomized rhesus macaques and blood from spleen-intact animals infected with P. coatneyi were examined by electron microscopy. In all three tissues, similar interactions (sequestration) between infected red blood cells (iRBC) and blood vessels were observed with evidence of rosette and auto-agglutinate formation. The iRBCs possessed caveolae similar to P. vivax and knob-like structures similar to P. falciparum. However, the knobs often appeared incompletely formed in the splenectomized animals in contrast to the intact knobs exhibited by spleen intact animals. Plasmodium coatneyi infection in the monkey replicates many of the ultrastructural features particularly associated with P. falciparum in humans and as such supports its use as a suitable animal model. However, the possible effect on host–parasite interactions and the pathogenesis of disease due to the use of splenectomized animals needs to be taken into consideration.
We present the data and initial results from the first pilot survey of the Evolutionary Map of the Universe (EMU), observed at 944 MHz with the Australian Square Kilometre Array Pathfinder (ASKAP) telescope. The survey covers
$270 \,\mathrm{deg}^2$
of an area covered by the Dark Energy Survey, reaching a depth of 25–30
$\mu\mathrm{Jy\ beam}^{-1}$
rms at a spatial resolution of
$\sim$
11–18 arcsec, resulting in a catalogue of
$\sim$
220 000 sources, of which
$\sim$
180 000 are single-component sources. Here we present the catalogue of single-component sources, together with (where available) optical and infrared cross-identifications, classifications, and redshifts. This survey explores a new region of parameter space compared to previous surveys. Specifically, the EMU Pilot Survey has a high density of sources, and also a high sensitivity to low surface brightness emission. These properties result in the detection of types of sources that were rarely seen in or absent from previous surveys. We present some of these new results here.
Repeated antigen testing of 12 severe acute respiratory coronavirus virus 2 (SARS-CoV-2)–positive nursing home residents using Abbott BinaxNOW identified 9 of 9 (100%) culture-positive specimens up to 6 days after initial positive test. Antigen positivity lasted 2–24 days. Antigen positivity might last beyond the infectious period, but it was reliable in residents with evidence of early infection.
The Quaternary Isotope Laboratory (QIL) at the University of Washington was launched in 1969 and directed by Minze Stuiver until his retirement in 1998. Here we review some of the scientific work undertaken in the QIL and the memories of some of Minze’s former students and colleagues.
The expansion of the Umayyad and Abbasid Caliphates (seventh to ninth centuries AD) brought diverse regions from the Indus Valley to the Eurasian Steppe under hegemonic control. An overlooked aspect of this political process is the subsequent translocation of species across ecological zones. This article explores species introduction in the early Islamic world, presenting the first archaeological evidence for domestic water buffalo in the Caucasus—identified using zooarchaeological and ZooMS methods on material from the historical site of Bardhaʿa in Azerbaijan. We contextualise these finds with historical accounts to demonstrate the exploitation of medieval marginal zones and the effects of centralised social reorganisation upon species dispersal.
Microscopic examination of blood smears remains the gold standard for laboratory inspection and diagnosis of malaria. Smear inspection is, however, time-consuming and dependent on trained microscopists with results varying in accuracy. We sought to develop an automated image analysis method to improve accuracy and standardization of smear inspection that retains capacity for expert confirmation and image archiving. Here, we present a machine learning method that achieves red blood cell (RBC) detection, differentiation between infected/uninfected cells, and parasite life stage categorization from unprocessed, heterogeneous smear images. Based on a pretrained Faster Region-Based Convolutional Neural Networks (R-CNN) model for RBC detection, our model performs accurately, with an average precision of 0.99 at an intersection-over-union threshold of 0.5. Application of a residual neural network-50 model to infected cells also performs accurately, with an area under the receiver operating characteristic curve of 0.98. Finally, combining our method with a regression model successfully recapitulates intraerythrocytic developmental cycle with accurate lifecycle stage categorization. Combined with a mobile-friendly web-based interface, called PlasmoCount, our method permits rapid navigation through and review of results for quality assurance. By standardizing assessment of Giemsa smears, our method markedly improves inspection reproducibility and presents a realistic route to both routine lab and future field-based automated malaria diagnosis.
Recent work has revived interest in the scattering matrix formulation of electron scattering in transmission electron microscopy as a stepping stone toward atomic-resolution structure determination in the presence of multiple scattering. We discuss ways of visualizing the scattering matrix that make its properties clear. Through a simulation-based case study incorporating shot noise, we shown how regularizing on this continuity enables the scattering matrix to be reconstructed from 4D scanning transmission electron microscopy (STEM) measurements from a single defocus value. Intriguingly, for crystalline samples, this process also yields the sample thickness to nanometer accuracy with no a priori knowledge about the sample structure. The reconstruction quality is gauged by using the reconstructed scattering matrix to simulate STEM images at defocus values different from that of the data from which it was reconstructed.
For the last two decades, high-dimensional data and methods have proliferated throughout the literature. Yet, the classical technique of linear regression has not lost its usefulness in applications. In fact, many high-dimensional estimation techniques can be seen as variable selection that leads to a smaller set of variables (a “submodel”) where classical linear regression applies. We analyze linear regression estimators resulting from model selection by proving estimation error and linear representation bounds uniformly over sets of submodels. Based on deterministic inequalities, our results provide “good” rates when applied to both independent and dependent data. These results are useful in meaningfully interpreting the linear regression estimator obtained after exploring and reducing the variables and also in justifying post-model-selection inference. All results are derived under no model assumptions and are nonasymptotic in nature.