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 no-reply@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.
Next generation high-power laser facilities are expected to generate hundreds-of-MeV proton beams and operate at multi-Hz repetition rates, presenting opportunities for medical, industrial and scientific applications requiring bright pulses of energetic ions. Characterizing the spectro-spatial profile of these ions at high repetition rates in the harsh radiation environments created by laser–plasma interactions remains challenging but is paramount for further source development. To address this, we present a compact scintillating fiber imaging spectrometer based on the tomographic reconstruction of proton energy deposition in a layered fiber array. Modeling indicates that spatial resolution of approximately 1 mm and energy resolution of less than 10% at proton energies of more than 20 MeV are readily achievable with existing 100 μm diameter fibers. Measurements with a prototype beam-profile monitor using 500 μm fibers demonstrate active readouts with invulnerability to electromagnetic pulses, and less than 100 Gy sensitivity. The performance of the full instrument concept is explored with Monte Carlo simulations, accurately reconstructing a proton beam with a multiple-component spectro-spatial profile.
New drugs to target different pathways in pulmonary hypertension has resulted in increased combination therapy, but details of this use in infants are not well described. In this large multicenter database study, we describe the pharmacoepidemiology of combination pulmonary vasodilator therapy in critically ill infants.
Methods:
We identified inborn infants discharged home from a Pediatrix neonatal ICU from 1997 to 2020 exposed to inhaled nitric oxide, sildenafil, epoprostenol, or bosentan for greater than two consecutive days. We compared clinical variables and drug utilisation between infants receiving simultaneous combination and monotherapy. We reported each combination’s frequency, timing, and duration and graphically represented drug use over time.
Results:
Of the 7681 infants that met inclusion criteria, 664 (9%) received combination therapy. These infants had a lower median gestational age and birth weight, were more likely to have cardiac and pulmonary anomalies, receive cardiorespiratory support, and had higher in-hospital mortality than those receiving monotherapy. Inhaled nitric oxide and sildenafil were most frequently used, and utilisation of combination and monotherapy for all drugs increased over time. Inhaled nitric oxide and epoprostenol were used in infants with a higher gestational age, earlier postnatal age, and shorter duration than sildenafil and bosentan. Dual therapy with inhaled nitric oxide and sildenafil was the most common combination therapy.
Conclusion:
Our study revealed an increased use of combination pulmonary vasodilator therapy, favouring inhaled nitric oxide and sildenafil, yet with considerable practice variation. Further research is needed to determine the optimal combination, sequence, dosing, and disease-specific indications for combination therapy.
Over the last 25 years, radiowave detection of neutrino-generated signals, using cold polar ice as the neutrino target, has emerged as perhaps the most promising technique for detection of extragalactic ultra-high energy neutrinos (corresponding to neutrino energies in excess of 0.01 Joules, or 1017 electron volts). During the summer of 2021 and in tandem with the initial deployment of the Radio Neutrino Observatory in Greenland (RNO-G), we conducted radioglaciological measurements at Summit Station, Greenland to refine our understanding of the ice target. We report the result of one such measurement, the radio-frequency electric field attenuation length $L_\alpha$. We find an approximately linear dependence of $L_\alpha$ on frequency with the best fit of the average field attenuation for the upper 1500 m of ice: $\langle L_\alpha \rangle = ( ( 1154 \pm 121) - ( 0.81 \pm 0.14) \, ( \nu /{\rm MHz}) ) \,{\rm m}$ for frequencies ν ∈ [145 − 350] MHz.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
Aims
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
Method
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
Results
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Conclusions
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Optical tracking systems typically trade off between astrometric precision and field of view. In this work, we showcase a networked approach to optical tracking using very wide field-of-view imagers that have relatively low astrometric precision on the scheduled OSIRIS-REx slingshot manoeuvre around Earth on 22 Sep 2017. As part of a trajectory designed to get OSIRIS-REx to NEO 101955 Bennu, this flyby event was viewed from 13 remote sensors spread across Australia and New Zealand to promote triangulatable observations. Each observatory in this portable network was constructed to be as lightweight and portable as possible, with hardware based off the successful design of the Desert Fireball Network. Over a 4-h collection window, we gathered 15 439 images of the night sky in the predicted direction of the OSIRIS-REx spacecraft. Using a specially developed streak detection and orbit determination data pipeline, we detected 2 090 line-of-sight observations. Our fitted orbit was determined to be within about 10 km of orbital telemetry along the observed 109 262 km length of OSIRIS-REx trajectory, and thus demonstrating the impressive capability of a networked approach to Space Surveillance and Tracking.
Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.
A developing application of laser-driven currents is the generation of magnetic fields of picosecond–nanosecond duration with magnitudes exceeding $B=10~\text{T}$. Single-loop and helical coil targets can direct laser-driven discharge currents along wires to generate spatially uniform, quasi-static magnetic fields on the millimetre scale. Here, we present proton deflectometry across two axes of a single-loop coil ranging from 1 to 2 mm in diameter. Comparison with proton tracking simulations shows that measured magnetic fields are the result of kiloampere currents in the coil and electric charges distributed around the coil target. Using this dual-axis platform for proton deflectometry, robust measurements can be made of the evolution of magnetic fields in a capacitor coil target.
Chronic suppurative otitis media is a massive public health problem in numerous low- and middle-income countries. Unfortunately, few low- and middle-income countries can offer surgical therapy.
Methods
A six-month long programme in Cambodia focused on training local surgeons in type I tympanoplasty was instigated. Qualitative educational and quantitative surgical outcomes were evaluated in the 12 months following programme completion. A four-month long training programme in mastoidectomy and homograft ossiculoplasty was subsequently implemented, and the preliminary surgical and educational outcomes were reported.
Results
A total of 124 patients underwent tympanoplasty by the locally trained surgeons. Tympanic membrane closure at six weeks post-operation was 88.5 per cent. Pure tone audiometry at three months showed that 80.9 per cent of patients had improved hearing, with a mean gain of 17.1 dB. The trained surgeons reported high confidence in performing tympanoplasty. Early outcomes suggest the local surgeons can perform mastoidectomy and ossiculoplasty as safely as overseas-trained surgeons, with reported surgeon confidence reflecting these positive outcomes.
Conclusion
The training programme has demonstrated success, as measured by surgeon confidence and operative outcomes. This approach can be emulated in other settings to help combat the global burden of chronic suppurative otitis media.
The diagenesis of Brent Group sandstones at Heather Field was studied to reconstruct time-dependent variations in reservoir quality, hydrodynamic history, and oil emplacement. Depositional facies, isotopic and trace-element composition of authigenic minerals, and present-day formation-water chemistry indicate several major changes in porewater chemistry related to both gravitational and compactional flow systems that significantly impacted diagenesis. Early cementation by calcite was related to influx of meteoric water and completely occludes porosity in certain areas of the Field, especially in lower reservoir zones. Geochemical, petrographic, and structural evidence indicate that average calcite precipitated at low to moderate temperature from reducing isotopically-depleted water having high levels of radiogenic Sr (40°–50°C, δ18O = −4 to −6‰, 87Sr/86Sr > 0·71). A major period of kaolinite precipitation and feldspar dissolution followed calcite cementation. The isotopic composition of pore-filling kaolinite shows Field-wide uniformity (δ18O average 13·8‰, δD average −53·2‰), suggesting thorough flushing of the reservoir by meteoric water and precipitation at low to moderate temperature (45°–60°C). Tectonic, burial, and thermal histories suggest that meteoric flushing occurred during the late-Cimmerian sea-level low, possibly in response to gravitational flow of meteoric water from exposed parts of the adjacent East Shetlands Platform. Illite and quartz diagenesis post-date kaolinite cementation, with illite K-Ar ages indicating precipitation through much of the Paleogene (55–27 Ma), coincident with migration of hydrocarbons from neighbouring sub-basins of the East Shetlands Basin. Illite stable isotopic data indicate precipitation in a system resulting from partial mixing of trapped meteoric pore-fluids with saline compaction water. The intensity of sandstone diagenesis is influenced by differences in the fluid migration history, content of detrital K-feldspar, and the time of hydrocarbon emplacement and results in spatial and temporal variations in reservoir quality.
Golden iridescent, <1–100 mm crystals of alternating lamellae of anthophyllite and gedrite constitute the bulk of orthoamphibolite pods within quartz-cordierite gneisses of the Akulleq terrane at Simiuttat, SW Greenland. X-ray powder diffraction powder gave a = 18.526(7),b = 17.979(15), c = 5.285(23) Å; a single crystal has a = 18.546(7), b = 17.950(16), c = 5.280(1) Å, space group Pnma with some reflections being notably broader than others. Spot EMPA yielded composite analyses: AlIV = 0.89–1.3, Mg/(Mg+Fe2+) = 0.57–0.61, Na/AlIV = 0.22–0.26. AFM imaging of {210} cleavage surfaces, showed a uniform corrugated morphology parallel to [001]; wavelength was 190–350 nm, mean 250 nm, amplitude 3 nm. A plan view resembles TEM images of (010)-parallel exsolution textures of orthoamphiboles. A second set of corrugations may crosscut the [001]-parallel ridges at 20–25°, akin to reported lamellar intergrowths developed parallel to both (010) and (120). Unequivocal evidence linking topography with lamellae is absent. In contrast to the conventional multi-layer reflector model, the ridged surface provides an additional origin for iridescence, acting as a diffraction grating. Included zircons, 50–10 μm, have Hf/Zr = 0.008–0.012, Hf+FeIIc. 0.16. 207Pb/206Pb ages are from 2690 to 2770 Ma, averaging 2732±10 Ma. Coexisting, included Th-, La-, Ce-, Pr-, Nd-, Gd-, Y-monazites have 207Pb/206Pb ages from 2680 to 2720 Ma, averaging 2707±12 Ma. The included crystals grew during a late Archaean metamorphism that produced overgrowths on zircons within gneisses to the north, but with Simiuttat grains showing a more complex history. The lamellae may have developed at the same time, or during a reheating c. 2550 Ma, or in a subsequent Proterozoic metamorphism.
A range of precision farming technologies are used commercially for variable rate applications of nitrogen (N) for cereals, yet these usually adjust N rates from a pre-set value, rather than predicting economically optimal N requirements on an absolute basis. This paper reports chessboard experiments set up to examine variation in N requirements, and to develop and test systems for its prediction, and to assess its predictability. Results showed very substantial variability in fertiliser N requirements within fields, typically >150 kg ha−1, and large variation in optimal yields, typically >2 t ha−1. Despite this, calculated increases in yield and gross margin with N requirements perfectly matched across fields were surprisingly modest (compared to the uniform average rate). Implications are discussed, including the causes of the large remaining variation in grain yield, after N limitations were removed.
An alternative origin and significance for kettle holes is considered. Kettles among some kame tracts may be due not to melt of buried ice but rather represent the location of ice pillars or roof pendants among stratified subglacial deposits.
There is consensus about the importance of ‘recovery’ in mental health services, but the link between recovery orientation of mental health teams and personal recovery of individuals has been underresearched.
Aims
To investigate differences in team leader, clinician and service user perspectives of recovery orientation of community adult mental health teams in England.
Method
In six English mental health National Health Service (NHS) trusts, randomly chosen community adult mental health teams were surveyed. A random sample of ten patients, one team leader and a convenience sample of five clinicians were surveyed from each team. All respondents rated the recovery orientation of their team using parallel versions of the Recovery Self Assessment (RSA). In addition, service users also rated their own personal recovery using the Questionnaire about Processes of Recovery (QPR).
Results
Team leaders (n = 22) rated recovery orientation higher than clinicians (n = 109) or patients (n = 120) (Wald(2) = 7.0, P = 0.03), and both NHS trust and team type influenced RSA ratings. Patient-rated recovery orientation was a predictor of personal recovery (b = 0.58, 95% CI 0.31–0.85, P<0.001). Team leaders and clinicians with experience of mental illness (39%) or supporting a family member or friend with mental illness (76%) did not differ in their RSA ratings from other team leaders or clinicians.
Conclusions
Compared with team leaders, frontline clinicians and service users have less positive views on recovery orientation. Increasing recovery orientation may support personal recovery.
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. In the absence of high-level evidence base for follow-up practices, the duration and frequency are often at the discretion of local centres. By reviewing the existing literature and collating experience from varying practices across the UK, this paper provides recommendations on the work up and management of lateral skull base cancer based on the existing evidence base for this rare condition.
Recommendations
• Patients should be followed up to a minimum of five years with a prolonged follow-up for selected patients. (G)
• Patients should be followed up at least two monthly in the first two years and three to six monthly in the subsequent years. (G)
• Patients should be seen in dedicated multidisciplinary head and neck oncology clinics. (G)
• Patients should be followed up by dedicated multidisciplinary clinical teams. (G)
• The multidisciplinary follow-up team should include clinical nurse specialists, speech and language therapists, dietitians and other allied health professionals in the role of key workers. (G)
• Clinical assessment should include adequate clinical examination including fibre-optic rigid or flexible nasopharyngolaryngoscopy. (R)
• Magnetic resonance imaging and positron emission tomography combined with computed tomography imaging should be used when recurrence is suspected. (R)
• Narrow band imaging can be used in the follow-up in selected sites. (R)
• Second primary tumours should be part of rationale of follow-up and therefore adequate screening strategies should be used to detect them. (G)
• Patients should be educated with regard to the appearance and detection of recurrences. (G)
• Patients with persistent pain should be investigated to exclude recurrent disease. (R)
• Patients should be offered support with tobacco and alcohol cessation services. (R)
Little is known about cause-specific long-term mortality beyond 30 days in pneumonia. We aimed to compare the mortality of patients with hospitalized pneumonia compared to age- and sex-matched controls beyond 30 days. Participants were drawn from the European Prospective Investigation into Cancer (EPIC)-Norfolk prospective population study. Hospitalized pneumonia cases were identified from record linkage (ICD-10: J12-J18). For this study we excluded people with hospitalized pneumonia who died within 30 days. Each case identified was matched to four controls and followed up until the end June 2012 (total 15 074 person-years, mean 6·1 years, range 0·08–15·2 years). Cox regression models were constructed to examine the all-cause, respiratory and cardiovascular mortality using date of pneumonia onset as baseline with binary pneumonia status as exposure. A total of 2465 men and women (503 cases, 1962 controls) [mean age (s.d.) 64·5 (8·3) years] were included in the study. Between a 30-day to 1-year period, hazard ratios (HRs) of all-cause and cardiovascular mortality were 7·3 [95% confidence interval (CI) 5·4–9·9] and 5·9 (95% CI 3·5–9·7), respectively (with very few respiratory deaths within the same period) in cases compared to controls after adjusting for age, sex, asthma, smoking status, pack years, systolic and diastolic blood pressure, diabetes, physical activity, waist-to-hip ratio, prevalent cardiovascular and respiratory diseases. All outcomes assessed also showed increased risk of death in cases compared to controls after 1 year; respiratory cause of death being the most significant during that period (HR 16·4, 95% CI 8·9–30·1). Hospitalized pneumonia was associated with increased all-cause and specific-cause mortality beyond 30 days.
We conducted infrared spectroscopic observations of bright stars in the direction of the molecular clouds W33 and GMC G23.3 − 0.3. We compared stellar spectro-photometric distances with parallactic distances to these regions, and we were able to assess the association of the detected massive stars with these molecular complexes. The spatial and temporal distributions of the detected stars enabled us to locate sources of ionizing radiation and to gather precise information on the star formation history of these clouds. The studied clouds present different distributions of massive stars.