Book chapters will be unavailable on Saturday 24th August between 8am-12pm BST. This is for essential maintenance which will provide improved performance going forwards. Please accept our apologies for any inconvenience caused.
To send 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 sending content to .
To send content items to your Kindle, first ensure email@example.com
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 sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent 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.
Determining infectious cross-transmission events in healthcare settings involves manual surveillance of case clusters by infection control personnel, followed by strain typing of clinical/environmental isolates suspected in said clusters. Recent advances in genomic sequencing and cloud computing now allow for the rapid molecular typing of infecting isolates.
To facilitate rapid recognition of transmission clusters, we aimed to assess infection control surveillance using whole-genome sequencing (WGS) of microbial pathogens to identify cross-transmission events for epidemiologic review.
Clinical isolates of Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, and Klebsiella pneumoniae were obtained prospectively at an academic medical center, from September 1, 2016, to September 30, 2017. Isolate genomes were sequenced, followed by single-nucleotide variant analysis; a cloud-computing platform was used for whole-genome sequence analysis and cluster identification.
Most strains of the 4 studied pathogens were unrelated, and 34 potential transmission clusters were present. The characteristics of the potential clusters were complex and likely not identifiable by traditional surveillance alone. Notably, only 1 cluster had been suspected by routine manual surveillance.
Our work supports the assertion that integration of genomic and clinical epidemiologic data can augment infection control surveillance for both the identification of cross-transmission events and the inclusion of missed and exclusion of misidentified outbreaks (ie, false alarms). The integration of clinical data is essential to prioritize suspect clusters for investigation, and for existing infections, a timely review of both the clinical and WGS results can hold promise to reduce HAIs. A richer understanding of cross-transmission events within healthcare settings will require the expansion of current surveillance approaches.
Buprenorphine (BUP)/samidorphan (SAM) combination is an opioid system modulator being investigated as an adjunctive treatment for major depressive disorder (MDD). BUP/SAM is a fixed-dose combination of BUP, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, and SAM, a µ-opioid receptor antagonist added to address the abuse and dependence potential of BUP.1,2
We assessed the effects of SAM on the abuse potential of BUP in the BUP/SAM combination in two ways: (1) a human abuse potential (HAP) study in volunteers; and (2) an evaluation of the clinical experience across studies of patients with MDD.
Study 212 (ClinicalTrials.gov ID: NCT02413281) was a HAP study in nondependent, recreational, adult opioid users. Following a qualification period, participants were randomized to 6 treatments in a blinded, crossover design: placebo (PBO), BUP/SAM at the target therapeutic dose (BUP/SAM 2mg/2mg), at 8mg/8mg and 16mg/16mg , and BUP alone (8mg and 16mg). The primary endpoint was maximum effect (Emax) for “At The Moment” Drug Liking Visual Analog Scale (VAS).
The clinical program for BUP/SAM included 4 PBO-controlled studies of patients with MDD (n=961). Pooled safety data were evaluated for adverse events (AEs) that may be associated with abuse, dependence, or withdrawal, as well as for objective signs of withdrawal with the Clinical Opioid Withdrawal Scale (COWS).
In Study 212 (n=38), Emax Drug Liking VAS scores for the BUP/SAM 2mg/2mg dose were similar to those for PBO (median within-subject difference [90% CI]: 2.5 [0.0–9.0]). Emax Drug Liking VAS scores for all BUP/SAM dose groups, including supratherapeutic doses, were significantly lower than those observed for either of the BUP doses. The supratherapeutic doses of BUP/SAM (8mg/8mg and 16mg/16mg) had higher Emax Drug Liking VAS scores than PBO, but the differences were small.
In the MDD controlled studies, the incidence of euphoria-related AEs was low for BUP/SAM 2mg/2mg and PBO (1.6% vs 0.2%, respectively) and there was no evidence of abuse or dependence behavior. Euphoria-related events typically occurred with treatment initiation and resolved with continued treatment. There was minimal evidence of withdrawal by reported AEs or COWS assessment.
These findings indicate that SAM mitigates the abuse potential of BUP in the BUP/SAM combination.
Inflammation of the mammary gland following bacterial infection, commonly known as mastitis, affects all mammalian species. Although the aetiology and epidemiology of mastitis in the dairy cow are well described, the genetic factors mediating resistance to mammary gland infection are not well known, due in part to the difficulty in obtaining robust phenotypic information from sufficiently large numbers of individuals. To address this problem, an experimental mammary gland infection experiment was undertaken, using a Friesian-Jersey cross breed F2 herd. A total of 604 animals received an intramammary infusion of Streptococcus uberis in one gland, and the clinical response over 13 milkings was used for linkage mapping and genome-wide association analysis. A quantitative trait locus (QTL) was detected on bovine chromosome 11 for clinical mastitis status using micro-satellite and Affymetrix 10 K SNP markers, and then exome and genome sequence data used from the six F1 sires of the experimental animals to examine this region in more detail. A total of 485 sequence variants were typed in the QTL interval, and association mapping using these and an additional 37 986 genome-wide markers from the Illumina SNP50 bovine SNP panel revealed association with markers encompassing the interleukin-1 gene cluster locus. This study highlights a region on bovine chromosome 11, consistent with earlier studies, as conferring resistance to experimentally induced mammary gland infection, and newly prioritises the IL1 gene cluster for further analysis in genetic resistance to mastitis.
Both direct observations and reconstructions from various datasets, suggest that conditions were radically different during the Maunder Minimum (MM) than during the space era. Using an MHD model, we develop a set of feasible solutions to infer the properties of the solar wind during this interval. Additionally, we use these results to drive a global magnetospheric model. Finally, using the 2008/2009 solar minimum as an upper limit for MM conditions, we use results from the International Reference Ionosphere (ILI) model to speculate on the state of the ionosphere. The results describe interplanetary, magnetospheric, and ionospheric conditions that were substantially different than today. For example: (1) the solar wind density and magnetic field strength were an order of magnitude lower; (2) the Earth’s magnetopause and shock standoff distances were a factor of two larger; and (3) the maximum electron density in the ionosphere was substantially lower.
Reconstructions of long-term solar variability underpin our understanding of the solar dynamo, potential tropospheric climate implications and future space weather scenarios. Prior to direct spacecraft measurements of the heliospheric magnetic field (HMF) and solar wind, accurate annual reconstructions are possible using geomagnetic and sunspot records. On longer timescales, information about the HMF can be extracted from cosmogenic radionuclide records, particularly 14C in ancient trees and 10Be in ice sheets. These proxies, and what they reveal about the HMF and solar wind, are briefly reviewed here.
The unique phenotypic and genetic aspects of obsessive-compulsive (OCD) and attention-deficit/hyperactivity disorder (ADHD) among individuals with Tourette syndrome (TS) are not well characterized. Here, we examine symptom patterns and heritability of OCD and ADHD in TS families.
OCD and ADHD symptom patterns were examined in TS patients and their family members (N = 3494) using exploratory factor analyses (EFA) for OCD and ADHD symptoms separately, followed by latent class analyses (LCA) of the resulting OCD and ADHD factor sum scores jointly; heritability and clinical relevance of the resulting factors and classes were assessed.
EFA yielded a 2-factor model for ADHD and an 8-factor model for OCD. Both ADHD factors (inattentive and hyperactive/impulsive symptoms) were genetically related to TS, ADHD, and OCD. The doubts, contamination, need for sameness, and superstitions factors were genetically related to OCD, but not ADHD or TS; symmetry/exactness and fear-of-harm were associated with TS and OCD while hoarding was associated with ADHD and OCD. In contrast, aggressive urges were genetically associated with TS, OCD, and ADHD. LCA revealed a three-class solution: few OCD/ADHD symptoms (LC1), OCD & ADHD symptoms (LC2), and symmetry/exactness, hoarding, and ADHD symptoms (LC3). LC2 had the highest psychiatric comorbidity rates (⩾50% for all disorders).
Symmetry/exactness, aggressive urges, fear-of-harm, and hoarding show complex genetic relationships with TS, OCD, and ADHD, and, rather than being specific subtypes of OCD, transcend traditional diagnostic boundaries, perhaps representing an underlying vulnerability (e.g. failure of top-down cognitive control) common to all three disorders.
Evidence from the Ross embayment, Antarctica, suggests an abrupt cooling and a concomitant increase in sea-ice cover at about 6000 BP (6 ka). Stable-isotope (δD) concentrations in the Taylor Dome ice core, at the western edge of the Ross embayment, decline rapidly after 6 ka, and continue to decline through the late Holocene. Methanesulfonic acid concentrations at Taylor Dome show opposite trends to δD Sediment cores from the western Ross Sea show a percentage minimum for the sea-ice diatom Fragilariopsis curta between 9 and 6 ka, whenTaylor Dome δD values are highest, followed by an increase through the late Holocene. Radiocarbon dates from raised beach deposits indicate that the retreat of ice shelves in the Ross embayment ceased at about 6 ka, coincident with the environmental changes inferred from the sediment and ice-core records. The similarity in timing suggests an important role for climate in controlling the evolution of ice-shelf margins following the end of the last glaciation.
Genetic–epidemiological studies that estimate the contributions of genetic factors to variation in tic symptoms are scarce. We estimated the extent to which genetic and environmental influences contribute to tics, employing various phenotypic definitions ranging between mild and severe symptomatology, in a large population-based adult twin-family sample.
In an extended twin-family design, we analysed lifetime tic data reported by adult mono- and dizygotic twins (n = 8323) and their family members (n = 7164; parents and siblings) from 7311 families in the Netherlands Twin Register. We measured tics by the abbreviated version of the Schedule for Tourette and Other Behavioral Syndromes. Heritability was estimated by genetic structural equation modeling for four tic disorder definitions: three dichotomous and one trichotomous phenotype, characterized by increasingly strictly defined criteria.
Prevalence rates of the different tic disorders in our sample varied between 0.3 and 4.5% depending on tic disorder definition. Tic frequencies decreased with increasing age. Heritability estimates varied between 0.25 and 0.37, depending on phenotypic definitions. None of the phenotypes showed evidence of assortative mating, effects of shared environment or non-additive genetic effects.
Heritabilities of mild and severe tic phenotypes were estimated to be moderate. Overlapping confidence intervals of the heritability estimates suggest overlapping genetic liabilities between the various tic phenotypes. The most lenient phenotype (defined only by tic characteristics, excluding criteria B, C and D of DSM-IV) rendered sufficiently reliable heritability estimates. These findings have implications in phenotypic definitions for future genetic studies.
Obsessive-compulsive disorder (OCD) is associated with an abnormally large error-related negativity (ERN), an electrophysiological measure of error monitoring in response to performance errors, but it is unclear if hoarding disorder (HD) also shows this abnormality. This study aimed to determine whether the neurophysiological mechanisms underlying error monitoring are similarly compromised in HD and OCD.
We used a visual flanker task to assess ERN in response to performance errors in 14 individuals with HD, 27 with OCD, 10 with HD+OCD, and 45 healthy controls (HC). Age-corrected performance and ERN amplitudes were examined using analyses of variance and planned pairwise group comparisons.
A main effect of hoarding on ERN (p = 0.031) was observed, indicating ERN amplitudes were attenuated in HD relative to non-HD subjects. A group × age interaction effect on ERN was also evident. In HD-positive subjects, ERN amplitude deficits were significantly greater in younger individuals (r = −0.479, p = 0.018), whereas there were no significant ERN changes with increasing age in OCD and HC participants.
The reduced ERN in HD relative to OCD and HC provides evidence that HD is neurobiologically distinct from OCD, and suggests that deficient error monitoring may be a core pathophysiological feature of HD. This effect was particularly prominent in younger HD participants, further suggesting that deficient error monitoring manifests most strongly early in the illness course and/or in individuals with a relatively early illness onset.
Cognitive reserve (CR) is a protective factor that supports cognition by increasing the resilience of an individual's cognitive function to the deleterious effects of cerebral lesions. A single environmental proxy indicator is often used to estimate CR (e.g. education), possibly resulting in a loss of the accuracy and predictive power of the investigation. Furthermore, while estimates of an individual's prior CR can be made, no operational measure exists to estimate dynamic change in CR resulting from exposure to new life experiences.
We aimed to develop two latent measures of CR through factor analysis: prior and current, in a sample of 467 healthy older adults.
The prior CR measure combined proxy measures traditionally associated with CR, while the current CR measure combined variables that had the potential to reflect dynamic change in CR due to new life experiences. Our main finding was that the analyses uncovered latent variables in hypothesized prior and current models of CR.
The prior CR model supports multivariate estimation of pre-existing CR and may be applied to more accurately estimate CR in the absence of neuropathological data. The current CR model may be applied to evaluate and explore the potential benefits of CR-based interventions prior to dementia onset.
To report a rare and unique presentation of metastatic breast cancer.
Case report and review of related literature.
A 62-year-old female with metastatic breast cancer, who had been free from recurrence for 4 years, presented with diplopia secondary to lateral rectus palsy. This was due to a sphenoid sinus metastasis, which was eroding into her cavernous sinus, resulting in VIth cranial nerve neuropathy.
All paranasal sinuses and the orbit are potential sites for metastases. Spread to the paranasal sinuses from breast cancer has been documented previously. However, we believe this to be the only reported case with lateral rectus palsy as a result of metastasis to the sphenoid sinus in which this was the only evidence of disseminated disease. Otolaryngology clinicians need to consider metastatic disease to the sinuses in patients with a history of neoplasia, but also recognise that tamoxifen treatment can itself cause visual disturbance.
Investigation of optical absorption in ∼25μm thick, monocrystalline silicon (Si) substrates obtained from a novel exfoliation technique is done by fabricating solar cells with single heterojunction architecture (without using intrinsic amorphous silicon layer) with diffused back junction and local back contact. The ease of process flow and the rugged and flexible nature of the substrates due to thick metal backing enables use of various light-trapping and optical absorption enhancement schemes traditionally practiced in the industry for thicker (>120μm) substrates. Optical measurement of solar cells using antireflective coating, texturing on both surfaces, and back surface dielectric/metal stack as mirror to reflect the long wavelength light from the back surface show a very low front surface reflectance of 4.6% in the broadband spectrum (300nm-1200nm). The illuminated current voltage (IV) and external quantum efficiency (EQE) measurement of such solar cell shows a high integrated current density of 34.4mA/cm2, which implies significant internal photon reflection. Our best cell with intrinsic amorphous silicon (i-a-Si) layer with only rear surface textured shows an efficiency of 14.9%. EQE data shows improved blue response and current density due to better front surface passivation. Simulations suggest that with optimized light trapping and surface passivation, such thin c-Si cells can reach efficiencies >20%.
The growth of of metallic copper by atomic layer deposition (ALD) using copper(I) di-sec-butylacetamidinate ([Cu(sBu-amd)]2) and molecular hydrogen (H2) on SiO2/Si surfaces has been studied. The mechanisms for the initial surface reaction and chemical bonding evolutions with each ALD cycle are inferred from in situ Fourier transform infrared spectroscopy (FTIR) data. Spectroscopic evidence for Cu agglomeration on SiO2 is presented involving the intensity variations of the SiO2 LO/TO phonon modes after chemical reaction with the Cu precursor and after the H2 precursor cycle. These intensity variations are observed over the first 20 ALD cycles at 185°C.
Twenty-two reference isolates and 30 local isolates of group A Streptococci were classified into 36 electrophoretic types (ET) on the basis of allozyme variation at 27 enzyme loci. Local isolates were characterized by a high frequency of M-non typable strains. M-type and ET were more closely associated in local isolates from an endemically-infected population; nevertheless, amongst the local isolates there were also strains of the same ET type with different M-types. A possible explanation is that genetic exchange between strains may introduce different M-types into strains of defined ET when these are exposed to strong selection in the presence of heavy loads of infection.
In contrast to the reported clustering of strains associated with toxic shock-like syndrome into two closely related ET clones, we found no relationship of ET phenotype to acute poststreptococcal glomerulonephritis or rheumatic fever.
Ribotyping with the restriction enzyme XbaI was used to study the dynamics of carriage of non-encapsulated Haemophilus influenzae (NCHi) in Aboriginal infants at risk of otitis media. Carriage rates of NCHi in the infants in the community were very high; the median age for detection was 50 days and colonization was virtually 100% by 120 days of age and persisted at a high level throughout the first year of life . Eighteen different ribotypes of NCHi were identified from 34 positive swabs taken from 3 infants over a period of 9 months. The same ribotypes were recovered for up to 3 months from consecutive swabs of individual infants, and 12 of 27 swabs (44·4%) yielded two ribotypes from four colonies typed. Statistical analysis suggested that most swabs would have been positive for two ribotypes if enough colonies had been typed although the second most frequent ribotype was detected on average in only 13% of strains. Early colonization and carriage of multiple ribotypes of NCHi may help to explain the chronicity of carriage and thus the persistence of otitis media in Aboriginal infants.
The view that most military personnel evacuated from war zones are suffering from combat stress reactions, or are otherwise traumatised by the horrors of war, has an impact on all aspects of military psychiatry.
To delineate the reasons for psychiatric aeromedical evacuation from Iraq from the start of build-up of UK forces in January 2003 until the end of October that year, 6 months after the end of formal hostilities.
A retrospective study was conducted of field and in-patient psychiatric assessments of 116 military personnel evacuated to the UK military psychiatric in-patient facility in Catterick Garrison.
Evacuees were mainly non-combatants (69%). A significant proportion were in reserve service (21%) and had a history of contact with mental health services (37%). Only 3% had a combat stress reaction. In over 85% of cases evacuation was for low mood attributed to separation from friends or family, or difficulties adjusting to the environment.
These findings have implications especially for screening for suitability for deployment, and for understanding any longer-term mental health problems arising in veterans from Iraq.