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Abstract This study provides an analysis of atmospheric neutrino oscillations at the ESSnuSB far detector facility. The prospects of the two cylindrical Water Cherenkov detectors with a total fiducial mass of 540 kt are investigated over 10 years of data taking in the standard three-flavor oscillation scenario. We present the confidence intervals for the determination of mass ordering, θ 23 octant as well as for the precisions on sin2 θ 23 and Δ m 31 2 $$ \left|\Delta {m}_{31}^2\right| $$ . It is shown that mass ordering can be resolved by 3σ CL (5σ CL) after 4 years (10 years) regardless of the true neutrino mass ordering. Correspondingly, the wrong θ 23 octant could be excluded by 3σ CL after 4 years (8 years) in the case where the true neutrino mass ordering is normal ordering (inverted ordering). The results presented in this work are complementary to the accelerator neutrino program in the ESSnuSB project.

Abstract Neutrino oscillation experiments provide a unique window in exploring several new physics scenarios beyond the standard three flavour. One such scenario is quantum decoherence in neutrino oscillation which tends to destroy the interference pattern of neutrinos reaching the far detector from the source. In this work, we study the decoherence in neutrino oscillation in the context of the ESSnuSB experiment. We consider the energy-independent decoherence parameter and derive the analytical expressions for P μe and P μμ probabilities in vacuum. We have computed the capability of ESSnuSB to put bounds on the decoherence parameters namely, Γ21 and Γ32 and found that the constraints on Γ21 are competitive compared to the DUNE bounds and better than the most stringent LBL ones from MINOS/MINOS+. We have also investigated the impact of decoherence on the ESSnuSB measurement of the Dirac CP phase δ CP and concluded that it remains robust in the presence of new physics.

Abstract The El Niño–Southern Oscillation (ENSO) teleconnection to Europe is projected to strengthen under global warming in most climate model simulations. However, given the current difference between recent observations and historical model simulations of tropical Pacific sea surface temperature trends, with models simulating an El Niño‐like warming in recent decades which is in disagreement with observations, it is important to understand the relative contributions of changes to the teleconnection forcing and background state to the overall teleconnection change. Using idealized climate model experiments, we show that both the eastward shift of El Niño precipitation and background state changes make contributions to the overall teleconnection change. These results suggest that the ENSO–Europe teleconnection can be expected to strengthen under global warming, even if ENSO precipitation anomalies do not shift eastwards as currently projected. However, the magnitude of the strengthening may depend on how much of an eastward shift does occur.

Abstract Precipitation projections in transient climate change scenarios have been extensively studied over multiple climate model generations. Although these simulations have also been used to make projections at specific Global Warming Levels (GWLs), dedicated simulations are more appropriate to study changes in a stabilizing climate. Here, we analyze precipitation projections in six multi‐century experiments with fixed atmospheric concentrations of greenhouse gases, conducted with the UK Earth System Model and which span a range of GWLs between 1.5 and 5°C of warming. Regions are identified where the sign of precipitation trends in high‐emission transient projections is reversed in the stabilization experiments. For example, stabilization reverses a summertime precipitation decline across Europe. This precipitation recovery occurs concurrently with changes in the pattern of Atlantic sea surface temperature trends due to a slow recovery of the Atlantic Meridional Overturning Circulation in the stabilization experiments, along with changes in humidity and atmospheric circulation.

Arctic sea ice is declining rapidly, but predictions of its future loss are made difficult by the large spread both in present-day and in future sea ice area and volume; hence, there is a need to better understand the drivers of model spread in sea ice state. Here we present a framework for understanding differences between modelled sea ice simulations based on attributing seasonal ice growth and melt differences. In the method presented, the net downward surface flux is treated as the principal driver of seasonal sea ice growth and melt. An energy balance approach is used to estimate the pointwise effect of model differences in key Arctic climate variables on this surface flux and hence on seasonal sea ice growth and melt. We compare three models with very different historical sea ice simulations: HadGEM2-ES, HadGEM3-GC3.1 and UKESM1.0. The largest driver of differences in ice growth and melt between these models is shown to be the ice area in summer (representing the surface albedo feedback) and the ice thickness distribution in winter (the thickness–growth feedback). Differences in snow and melt pond cover during the early summer exert a smaller effect on the seasonal growth and melt, hence representing the drivers of model differences in both this and in the sea ice volume. In particular, the direct impacts on sea ice growth and melt of differing model parameterisations of snow area and of melt ponds are shown to be small but non-negligible.

Abstract In this paper, we present the physics performance of the ESSnuSB experiment in the standard three flavor scenario using the updated neutrino flux calculated specifically for the ESSnuSB configuration and updated migration matrices for the far detector. Taking conservative systematic uncertainties corresponding to a normalization error of $$5\%$$ 5 % for signal and $$10\%$$ 10 % for background, we find that there is $$10\sigma $$ 10 σ $$(13\sigma )$$ ( 13 σ ) CP violation discovery sensitivity for the baseline option of 540 km (360 km) at $$\delta _\mathrm{CP} = \pm 90^\circ $$ δ CP = ± 90 ∘ . The corresponding fraction of $$\delta _\mathrm{CP}$$ δ CP for which CP violation can be discovered at more than $$5 \sigma $$ 5 σ is $$70\%$$ 70 % . Regarding CP precision measurements, the $$1\sigma $$ 1 σ error associated with $$\delta _\mathrm{CP} = 0^\circ $$ δ CP = 0 ∘ is around $$5^\circ $$ 5 ∘ and with $$\delta _\mathrm{CP} = -90^\circ $$ δ CP = - 90 ∘ is around $$14^\circ $$ 14 ∘ $$(7^\circ )$$ ( 7 ∘ ) for the baseline option of 540 km (360 km). For hierarchy sensitivity, one can have $$3\sigma $$ 3 σ sensitivity for 540 km baseline except $$\delta _\mathrm{CP} = \pm 90^\circ $$ δ CP = ± 90 ∘ and $$5\sigma $$ 5 σ sensitivity for 360 km baseline for all values of $$\delta _\mathrm{CP}$$ δ CP . The octant of $$\theta _{23}$$ θ 23 can be determined at $$3 \sigma $$ 3 σ for the values of: $$\theta _{23} > 51^\circ $$ θ 23 > 51 ∘ ( $$\theta _{23} < 42^\circ $$ θ 23 < 42 ∘ and $$\theta _{23} > 49^\circ $$ θ 23 > 49 ∘ ) for baseline of 540 km (360 km). Regarding measurement precision of the atmospheric mixing parameters, the allowed values at $$3 \sigma $$ 3 σ are: $$40^\circ< \theta _{23} < 52^\circ $$ 40 ∘ < θ 23 < 52 ∘ ( $$42^\circ< \theta _{23} < 51.5^\circ $$ 42 ∘ < θ 23 < 51 . 5 ∘ ) and $$2.485 \times 10^{-3}$$ 2.485 × 10 - 3 eV $$^2< \varDelta m^2_{31} < 2.545 \times 10^{-3}$$ 2 < Δ m 31 2 < 2.545 × 10 - 3 eV $$^2$$ 2 ( $$2.49 \times 10^{-3}$$ 2.49 × 10 - 3 eV $$^2< \varDelta m^2_{31} < 2.54 \times 10^{-3}$$ 2 < Δ m 31 2 < 2.54 × 10 - 3 eV $$^2$$ 2 ) for the baseline of 540 km (360 km).

The future of the Antarctic Ice Sheet in response to climate warming is one of the largest sources of uncertainty in estimates of future changes in global mean sea level (ΔGMSL). Mass loss is currently concentrated in regions of warm circumpolar deep water, but it is unclear how ice shelves currently surrounded by relatively cold ocean waters will respond to climatic changes in the future. Studies suggest that warm water could flush the Filchner–Ronne (FR) ice shelf cavity during the 21st century, but the inland ice sheet response to a drastic increase in ice shelf melt rates is poorly known. Here, we use an ice flow model and uncertainty quantification approach to project the GMSL contribution of the FR basin under RCP emissions scenarios, and we assess the forward propagation and proportional contribution of uncertainties in model parameters (related to ice dynamics and atmospheric/oceanic forcing) on these projections. Our probabilistic projections, derived from an extensive sample of the parameter space using a surrogate model, reveal that the FR basin is unlikely to contribute positively to sea level rise by the 23rd century. This is primarily due to the mitigating effect of increased accumulation with warming, which is capable of suppressing ice loss associated with ocean-driven increases in sub-shelf melt. Mass gain (negative ΔGMSL) from the FR basin increases with warming, but uncertainties in these projections also become larger. In the highest emission scenario RCP8.5, ΔGMSL is likely to range from −103 to 26 mm, and this large spread can be apportioned predominantly to uncertainties in parameters driving increases in precipitation (30 %) and sub-shelf melting (44 %). There is potential, within the bounds of our input parameter space, for major collapse and retreat of ice streams feeding the FR ice shelf, and a substantial positive contribution to GMSL (up to approx. 300 mm), but we consider such a scenario to be very unlikely. Adopting uncertainty quantification techniques in future studies will help to provide robust estimates of potential sea level rise and further identify target areas for constraining projections.

We describe a case of left hand extensor tenosynovitis due to histoplasmosis in a patient with dermatomyositis on chronic immunosuppression. Treatment involved surgical debridement and antifungal therapy. The patient experienced paradoxical worsening of tenosynovial inflammation during de-augmentation of immunosuppression felt to be immune reconstitution inflammatory syndrome.

ESSnuSB is a design study for an experiment to measure the CP violation in the leptonic sector at the second neutrino oscillation maximum using a neutrino beam driven by the uniquely powerful ESS linear accelerator. The reduced impact of systematic errors on sensitivity at the second maximum allows for a very precise measurement of the CP violating parameter. This review describes the fundamental advantages of measurement at the second maximum, the necessary upgrades to the ESS linac in order to produce a neutrino beam, the near and far detector complexes, and the expected physics reach of the proposed ESSnuSB experiment, concluding with the near future developments aimed at the project realization.

A simple diagnostic cloud scheme (SimCloud) for general circulation models (GCMs), which has a modest level of complexity and is transparent in describing its dependence on tunable parameters, is proposed in this study. The large-scale clouds, which form the core of the scheme, are diagnosed from relative humidity. In addition, the marine low stratus clouds, typically found off the west coast of continents over subtropical oceans, are determined largely as a function of inversion strength. A “freeze-dry” adjustment based on a simple function of specific humidity is also available to reduce an excessive cloud bias in polar regions. Other cloud properties, such as the effective radius of cloud droplet and cloud liquid water content, are specified as simple functions of temperature. All of these features are user-configurable. The cloud scheme is implemented in Isca, a modeling framework designed to enable the construction of GCMs at varying levels of complexity, but could readily be adapted to other GCMs. Simulations using the scheme with realistic continents generally capture the observed structure of cloud fraction and cloud radiative effect (CRE), as well as its seasonal variation. Specifically, the explicit low-cloud scheme improves the simulation of shortwave CREs over the eastern subtropical oceans by increasing the cloud fraction and cloud water path. The freeze-dry adjustment alleviates the longwave CRE biases in polar regions, especially in winter. However, the longwave CRE in tropical regions and shortwave CRE over the extratropics are both still too strong compared to observations. Nevertheless, this simple cloud scheme provides a suitable basis for examining the impacts of clouds on climate in idealized modeling frameworks.

A new method of sea ice model evaluation is demonstrated. Data from the network of Arctic ice mass balance buoys (IMBs) are used to estimate distributions of vertical energy fluxes over sea ice in two densely sampled regions – the North Pole and Beaufort Sea. The resulting dataset captures seasonal variability in sea ice energy fluxes well, and it captures spatial variability to a lesser extent. The dataset is used to evaluate a coupled climate model, HadGEM2-ES (Hadley Centre Global Environment Model, version 2, Earth System), in the two regions. The evaluation shows HadGEM2-ES to simulate too much top melting in summer and too much basal conduction in winter. These results are consistent with a previous study of sea ice state and surface radiation in this model, increasing confidence in the IMB-based evaluation. In addition, the IMB-based evaluation suggests an additional important cause for excessive winter ice growth in HadGEM2-ES, a lack of sea ice heat capacity, which was not detectable in the earlier study. Uncertainty in the IMB fluxes caused by imperfect knowledge of ice salinity, snow density and other physical constants is quantified (as is inaccuracy due to imperfect sampling of ice thickness) and in most cases is found to be small relative to the model biases discussed. Hence the IMB-based evaluation is shown to be a valuable tool with which to analyse sea ice models and, by extension, better understand the large spread in coupled model simulations of the present-day ice state. Reducing this spread is a key task both in understanding the current rapid decline in Arctic sea ice and in constraining projections of future Arctic sea ice change.

Background Informed consent is an integral part of clinical practice. There is widespread agreement amongst health professionals that obtaining procedural consent needs to move away from a unidirectional transfer of information to a process of supporting patients in making informed, self‐determined decisions. This review aimed to identify processes and measures that warrant consideration when engaging in consent‐based discussions with competent patients undergoing elective procedures. Methods Formal written guidance from the General Medical Council and Royal College of Surgeons of England, in addition to peer‐reviewed literature and case law, was considered in the formulation of this review. Results A framework for obtaining consent is presented that is informed by the key tenets of shared decision‐making (SDM), a model that advocates the contribution of both the clinician and patient to the decision‐making process through emphasis on patient participation, analysis of empirical evidence, and effective information exchange. Moreover, areas of contention are highlighted in which further guidance and research are necessary for improved enhancement of the consent process. Conclusion This SDM‐centric framework provides structure, detail and suggestions for achieving meaningful consent.

A new framework is presented for analysing the proximate causes of model Arctic sea ice biases, demonstrated with the CMIP5 model HadGEM2-ES (Hadley Centre Global Environment Model version 2 – Earth System). In this framework the Arctic sea ice volume is treated as a consequence of the integrated surface energy balance, via the volume balance. A simple model allows the local dependence of the surface flux on specific model variables to be described as a function of time and space. When these are combined with reference datasets, it is possible to estimate the surface flux bias induced by the model bias in each variable. The method allows the role of the surface albedo and ice thickness–growth feedbacks in sea ice volume balance biases to be quantified along with the roles of model bias in variables not directly related to the sea ice volume. It shows biases in the HadGEM2-ES sea ice volume simulation to be due to a bias in spring surface melt onset date, partly countered by a bias in winter downwelling longwave radiation. The framework is applicable in principle to any model and has the potential to greatly improve understanding of the reasons for ensemble spread in the modelled sea ice state. A secondary finding is that observational uncertainty is the largest cause of uncertainty in the induced surface flux bias calculation.

A super-ensemble methodology is proposed to improve the quality of short-term ocean analyses for sea surface temperature (SST) in the Mediterranean Sea. The methodology consists of a multiple linear regression technique applied to a multi-physics multi-model super-ensemble (MMSE) data set. This is a collection of different operational forecasting analyses together with ad hoc simulations, created by modifying selected numerical model parameterizations. A new linear regression algorithm based on empirical orthogonal function filtering techniques is shown to be efficient in preventing overfitting problems, although the best performance is achieved when a simple spatial filter is applied after the linear regression. Our results show that the MMSE methodology improves the ocean analysis SST estimates with respect to the best ensemble member (BEM) and that the performance is dependent on the selection of an unbiased operator and the length of training. The quality of the MMSE data set has the largest impact on the MMSE analysis root mean square error (RMSE) evaluated with respect to observed satellite SST. The MMSE analysis estimates are also affected by training period length, with the longest period leading to the smoothest estimates. Finally, lower RMSE analysis estimates result from the following: a 15-day training period, an overconfident MMSE data set (a subset with the higher-quality ensemble members) and the least-squares algorithm being filtered a posteriori.

Recent decades have seen significant developments in climate prediction capabilities at seasonal-to-interannual timescales. However, until recently the potential of such systems to predict Arctic climate had rarely been assessed. This paper describes a multi-model predictability experiment which was run as part of the Arctic Predictability and Prediction On Seasonal to Interannual Timescales (APPOSITE) project. The main goal of APPOSITE was to quantify the timescales on which Arctic climate is predictable. In order to achieve this, a coordinated set of idealised initial-value predictability experiments, with seven general circulation models, was conducted. This was the first model intercomparison project designed to quantify the predictability of Arctic climate on seasonal to interannual timescales. Here we present a description of the archived data set (which is available at the British Atmospheric Data Centre), an assessment of Arctic sea ice extent and volume predictability estimates in these models, and an investigation into to what extent predictability is dependent on the initial state. The inclusion of additional models expands the range of sea ice volume and extent predictability estimates, demonstrating that there is model diversity in the potential to make seasonal-to-interannual timescale predictions. We also investigate whether sea ice forecasts started from extreme high and low sea ice initial states exhibit higher levels of potential predictability than forecasts started from close to the models' mean state, and find that the result depends on the metric. Although designed to address Arctic predictability, we describe the archived data here so that others can use this data set to assess the predictability of other regions and modes of climate variability on these timescales, such as the El Niño–Southern Oscillation.

Water isotope-enabled coupled atmosphere–ocean climate models allow for exploration of the relative contributions to coral stable oxygen isotope (δ18Ocoral) variability arising from sea surface temperature (SST) and the isotopic composition of seawater (δ18Osw). The unforced behaviour of the isotope-enabled HadCM3 coupled general circulation model suggests that the extent to which inter-annual δ18Osw variability contributes to that in model δ18Ocoral is strongly spatially dependent, ranging from being negligible in the eastern equatorial Pacific to accounting for 50% of δ18Ocoral variance in parts of the western Pacific. In these latter cases, a significant component of the inter-annual δ18Osw variability is correlated to that in SST, meaning that local calibrations of the effective local δ18Ocoral–SST relationships are likely to be essential. Furthermore, the relationship between δ18Osw and SST can be non-linear, such that the model interpretation of central and western equatorial Pacific δ18Ocoral in the context of a linear dependence on SST alone leads to overestimation (by up to 20%) of the SST anomalies associated with large El Niño events. Intra-model evaluation of a salinity-based pseudo-coral approach shows that such an approach captures the first-order features of the model δ18Osw behaviour. However, the utility of the pseudo-corals is limited by the extent of spatial variability seen within the modelled slopes of the temporal salinity–δ18Osw relationship.

Spatially-explicit maps of aboveground biomass are essential for calculating the losses and gains in forest carbon at a regional to national level. The production of such maps across wide areas will become increasingly necessary as international efforts to protect primary forests, such as the REDD+ (Reducing Emissions from Deforestation and forest Degradation) mechanism, come into effect, alongside their use for management and research more generally. However, mapping biomass over high-biomass tropical forest is challenging as (1) direct regressions with optical and radar data saturate, (2) much of the tropics is persistently cloud-covered, reducing the availability of optical data, (3) many regions include steep topography, making the use of radar data complex, (5) while LiDAR data does not suffer from saturation, expensive aircraft-derived data are necessary for complete coverage. We present a solution to the problems, using a combination of terrain-corrected L-band radar data (ALOS PALSAR), spaceborne LiDAR data (ICESat GLAS) and ground-based data. We map Gabon's Lopé National Park (5000 km2) because it includes a range of vegetation types from savanna to closed-canopy tropical forest, is topographically complex, has no recent contiguous cloud-free high-resolution optical data, and the dense forest is above the saturation point for radar. Our 100 m resolution biomass map is derived from fusing spaceborne LiDAR (7142 ICESat GLAS footprints), 96 ground-based plots (average size 0.8 ha) and an unsupervised classification of terrain-corrected ALOS PALSAR radar data, from which we derive the aboveground biomass stocks of the park to be 78 Tg C (173 Mg C ha−1). This value is consistent with our field data average of 181 Mg C ha−1, from the field plots measured in 2009 covering a total of 78 ha, and which are independent as they were not used for the GLAS-biomass estimation. We estimate an uncertainty of &pm;25% on our carbon stock value for the park. This error term includes uncertainties resulting from the use of a generic tropical allometric equation, the use of GLAS data to estimate Lorey's height, and the necessity of separating the landscape into distinct classes. As there is currently no spaceborne LiDAR satellite in operation (GLAS data is available for 2003–2009 only), this methodology is not suitable for change-detection. This research underlines the need for new satellite LiDAR data to provide the potential for biomass-change estimates, although this need will not be met before 2015.

We present joint probability distribution functions of future seasonal-mean changes in surface air temperature and precipitation for the European region for the SRES A1B emissions scenario. The probabilistic projections quantify uncertainties in the leading physical, chemical and biological feedbacks and combine information from perturbed physics ensembles, multi-model ensembles and observations.

It has been shown previously that one member of the Met Office Hadley Centre single-parameter perturbed physics ensemble – the so-called "low entrainment parameter" member – has a much higher climate sensitivity than other individual parameter perturbations. Here we show that the concentration of stratospheric water vapour in this member is over three times higher than observations, and, more importantly for climate sensitivity, increases significantly when climate warms. The large surface temperature response of this ensemble member is more consistent with stratospheric humidity change, rather than upper tropospheric clouds as has been previously suggested. The direct relationship between the bias in the control state (elevated stratospheric humidity) and the cause of the high climate sensitivity (a further increase in stratospheric humidity) lends further doubt as to the realism of this particular integration. This, together with other evidence, lowers the likelihood that the climate system's physical sensitivity is significantly higher than the likely upper range quoted in the Intergovernmental Panel on Climate Change's Fourth Assessment Report.

We examine the behaviour of the El Niño – Southern Oscillation (ENSO) in an ensemble of global climate model simulations with perturbations to parameters in the atmosphere and ocean components respectively. The influence of the uncertainty in these parametrisations on ENSO are investigated systematically. The ensemble exhibits a range of different ENSO behaviour in terms of the amplitude and spatial structure of the sea surface temperature (SST) variability. The nature of the individual feedbacks that operate within the ENSO system are diagnosed using an Intermediate Complexity Model (ICM), which has been used previously to examine the diverse ENSO behaviour of the CMIP3 multi-model ensemble. Unlike in that case, the ENSO in these perturbed physics experiments is not principally controlled by variations in the mean climate state. Rather the parameter perturbations influence the ENSO characteristics by modifying the coupling feedbacks within the cycle. The associated feedbacks that contribute most to the ensemble variations are the response of SST to local wind variability and damping, followed by the response of SST to thermocline anomalies and the response of the zonal wind stress to those SST anomalies. Atmospheric noise amplitudes and oceanic processes play a relatively minor role.

The sensitivity of El Niño-Southern Oscillation (ENSO) to changes in mean climate is investigated for simulations of pre-industrial and mid-Holocene (6000 years before present) climate using the Hadley Centre coupled atmosphere-ocean model, HadCM3. Orbitally-forced changes in insolation in the mid-Holocene produce changes in seasonality which may alter ENSO amplitude and frequency. The model simulations are compared with mid-Holocene fossil coral oxygen isotope records from the western Pacific Warm Pool. The coral records imply a reduction of around 60% in the amplitude of interannual variability associated with ENSO in the mid-Holocene, while the model simulates a smaller reduction in ENSO amplitude of around 10%. The model also simulates a slight shift to longer period variability and a weakening of ENSO phase-locking to the seasonal cycle in the mid-Holocene. There is little change in the pattern of ENSO tropical precipitation teleconnections in the simulated mid-Holocene climate.

Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up. Patients and methods: 3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1:1 basis to standard adjuvant systemic therapy +/− intravenous ZOL 4 mg every 3–4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects. Results: With a median follow up of 117 months [IQR 70.4–120.4), DFS and IDFS were similar in both arms (HRDFS = 0.94, 95%CI = 0.84–1.06, p = 0.340; HRIDFS = 0.91, 95%CI = 0.82–1.02, p = 0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFS = 0.82, 95%CI = 0.67–1.00; HRIDFS = 0.78, 95%CI = 0.64–0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFS = 0.75, 95%CI = 0.58–0.97) and OS HROS = 0.69, 95%CI = 0.50–0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISH + tumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFS = 0.76, 95%CI = 0.63–0.92, p = 0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred. Conclusions: Disease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.

Lysine deacetylases (KDACs or HDACs) are metal‐dependent enzymes that regulate lysine acetylation, a post‐translational modification that is present on thousands of human proteins, essential for many cellular processes, and often misregulated in diseases. The selective inhibition of KDACs would allow for understanding of the biological roles of individual KDACs and therapeutic targeting of individual enzymes. Recent studies have suggested that purportedly specific KDAC inhibitors have significant off‐target binding, but the biological consequences of off‐target binding were not evaluated. We compared the effects of treatment with two of the reportedly most KDAC‐selective inhibitors, Tubastatin A and PCI‐34051, in HT1080 cells in which the endogenous KDAC6 or KDAC8 gene has been mutated to inactivate enzyme catalysis while retaining enzyme expression. Genetic inactivation results in much stronger deacetylation defects on known targets compared to inhibitor treatment. Gene expression analysis revealed that both inhibitors have extensive and extensively overlapping off‐target effects in cells, even at low inhibitor doses. Furthermore, Tubastatin A treatment led to increased histone acetylation, while inactivation of KDAC6 or KDAC8 did not. Genetic inactivation of KDAC6, but not KDAC8, impaired tumor formation in a xenograft model system, in contrast to previous reports with KDAC inhibitors suggesting the reverse. We conclude that the majority of observed biological effects of treatment with KDAC inhibitors are due to off‐target effects rather than the intended KDAC inhibition. Developing a truly specific KDAC6 inhibitor could be a promising therapeutic avenue, but it is imperative to develop new inhibitors that selectively mimic genetic inactivation of individual KDACs.

A unique stratigraphic sequence of fossil leaves of Eotrigonobalanus furcinervis (extinct trees of the beech family, Fagaceae) from central Germany has been used to derive an atmospheric pCO2 record with multiple data points spanning the late middle to late Eocene, two sampling levels which may be earliest Oligocene, and two samples from later in the Oligocene. Using the inverse relationship between the density of stomata and pCO2, we show that pCO2 decreased continuously from the late middle to late Eocene, reaching a relatively stable low value before the end of the Eocene. Based on the subsequent records, pCO2 in parts of the Oligocene was similar to latest Eocene values. These results suggest that a decrease in pCO2 preceded the large shift in marine oxygen isotope records that characterizes the Eocene–Oligocene transition and that when a certain threshold of pCO2 change was crossed, the cumulative effects of this and other factors resulted in rapid temperature decline, ice build up on Antarctica and hence a change of climate mode.

Abstract Adaptation is essential to mitigate the effects of climate change, such as increasing flood risk. In response to widespread maladaptation, citizen-led approaches are increasingly championed, whereby people on the frontline of climate change determine their own objectives and strategies of adaptation. Enabling equitable and effective citizen-led adaptation requires an understanding of the barriers for different groups of people but this is currently lacking, especially in low- and middle-income countries. Using responses to a co-produced household survey (n = 286) in Tamale, Ghana, we show that barriers to citizen-led adaptation interventions (n = 11) differ between households which we relate to important components of adaptive capacity. Overall, awareness, education, and networks are the most important barriers, but resources and time are important for poor households of fewer members. Barriers also differ between interventions and overall structural interventions are preferred over behavioural. This work can inform policies and actions to support effective and equitable citizen-led adaptation.

Abstract Background 4-methylimidazole is a ubiquitous and potentially carcinogenic environmental toxicant. Genetic factors that contribute to variation in susceptibility to its toxic effects are challenging to assess in human populations. We used the Drosophila melanogaster Genetic Reference Panel (DGRP), a living library of natural genetic variation, to identify genes with human orthologs associated with variation in susceptibility to 4-methylimidazole. Results We screened 204 DGRP lines for survival following 24-hour exposure to 4-methylimidazole. We found extensive genetic variation for survival, with a broad sense heritability of 0.82; as well as genetic variation in sexual dimorphism, with a cross-sex genetic correlation of 0.59. Genome-wide association analyses identified a total of 241 candidate molecular polymorphisms in or near 273 unique genes associated with survival. These polymorphisms had either sex-specific or sex-antagonistic effects, and most had putative regulatory effects. We generated interaction networks using these candidate genes as inputs and computationally recruited genes with known physical or genetic interactions. The network genes were significantly over-represented for gene ontology terms involving all aspects of development (including nervous system development) and cellular and organismal functions as well as canonical signaling pathways, and most had human orthologs. Conclusions The genetic basis of variation in sensitivity to acute exposure to 4-methylimidazole in Drosophila is attributable to variation in genes and networks of genes known for their effects on multiple developmental and cellular processes, including possible neurotoxicity. Given evolutionary conservation of the underlying genes and pathways, these insights may be applicable to humans.

Basal materials in ice cores hold information about paleoclimate conditions, glacial processes, and the timing of past ice-free intervals, all of which aid understanding of ice sheet stability and its contribution to sea level rise in a warming climate. Only a few cores have been drilled through ice sheets into the underlying sediment and bedrock, producing limited material for analysis. The last of three Camp Century ice cores, which the U.S. Army collected in northwestern Greenland from 1963–1966 CE, recovered about 3.5 m of subglacial material, including ice and sediment. Here, we document the scientific history of the Camp Century subglacial material. We present our recent core-cutting, sub-sampling, and processing methodology and results for this unique archive. In 1972 CE, curators at the Buffalo, New York, Ice Core Laboratory cut the original core sections into 32 segments that were each about 10 cm long. Since then, two segments were lost and are unaccounted for, two were thawed, and two were cut as pilot samples in 2019 CE. Except for the two thawed segments, the rest of the extant core has remained frozen since collection. In 2021 CE, we documented, described, and then cut each of the remaining frozen archived segments (n=26). We saved an archival half and cut the working half into eight oriented sub-samples under controlled temperature and light conditions for physical, geochemical, isotopic, sedimentological, magnetic, and biological analyses. Our approach was designed to maximize sample usage for multiproxy analysis, minimize contamination, and preserve archive material for future analyses of this legacy subglacial material. Grain size, bulk density, sedimentary features, magnetic susceptibility, and ice content, as well as pore ice pH and conductivity, suggest that the basal sediment contains five stratigraphic units. We interpret these stratigraphic units as representing different depositional environments in subglacial or ice-free conditions: from bottom to top, a diamicton with subhorizontal ice lenses (Unit 1), vertically fractured ice with dispersed fine-grained sediments (<20 % in mass) (Unit 2), a normally graded bed of pebbles to very fine sand in an icy matrix (Unit 3), bedded very fine to fine sand (Unit 4), and stratified medium to coarse sand (Unit 5). Plant macrofossils are present in all samples and are most abundant in Units 3 and 4; insect remains are present in some samples (Units 1, 3, and 5). Our approach provides a working template for future studies of ice core basal materials because it includes intentional planning of core sub-sampling, processing methodologies, and archiving strategies to optimize the collection of paleoclimate, glacial process, geochemical, geochronological, and sediment properties from archives of limited size. Our work benefited from a carefully curated and preserved archive, allowing the application of analytical techniques not available in 1966 CE. Preserving uncontaminated core material for future analyses that use currently unavailable tools and techniques is an important consideration for rare archive materials such as these from Camp Century.

ObjectiveAge-related hippocampal atrophy is associated with memory loss in older adults, and certain hippocampal subfields are more vulnerable to age-related atrophy than others. Cardiorespiratory fitness (CRF) may be an important protective factor for preserving hippocampal volume, but little is known about how CRF relates to the volume of specific hippocampal subfields, and whether associations between CRF and hippocampal subfield volumes are related to episodic memory performance. To address these gaps, the current study evaluates the associations among baseline CRF, hippocampal subfield volumes, and episodic memory performance in cognitively unimpaired older adults from the Investigating Gains in Neurocognition Trial of Exercise (IGNITE) (NCT02875301).MethodsParticipants (N = 601, ages 65–80, 72% female) completed assessments including a graded exercise test measuring peak oxygen comsumption (VO2peak) to assess CRF, cognitive testing, and high-resolution magnetic resonance imaging of the hippocampus processed with Automated Segmentation of Hippocampal Subfields (ASHS). Separate linear regression models examined whether CRF was associated with hippocampal subfield volumes and whether those assocations were moderated by age or sex. Mediation models examined whether hippocampal volumes statistically mediated the relationship between CRF and episodic memory performance. Covariates included age, sex, years of education, body mass index, estimated intracranial volume, and study site.ResultsHigher CRF was significantly associated with greater total left (B = 5.82, p = 0.039) and total right (B = 7.64, p = 0.006) hippocampal volume, as well as greater left CA2 (B = 0.14, p = 0.022) and dentate gyrus (DG; B = 2.34, p = 0.031) volume, and greater right CA1 (B = 3.99, p = 0.011), CA2 (B = 0.15, p = 0.002), and subiculum (B = 1.56, p = 0.004) volume. Sex significantly moderated left DG volume (B = −4.26, p = 0.017), such that the association was positive and significant only for males. Total left hippocampal volume [indirect effect = 0.002, 95% CI (0.0002, 0.00), p = 0.027] and right subiculum volume [indirect effect = 0.002, 95% CI (0.0007, 0.01), p = 0.006] statistically mediated the relationship between CRF and episodic memory performance.DiscussionWhile higher CRF was significantly associated with greater total hippocampal volume, CRF was not associated with all underlying subfield volumes. Our results further demonstrate the relevance of the associations between CRF and hippocampal volume for episodic memory performance. Finally, our results suggest that the regionally-specific effects of aging and Alzheimer’s disease on hippocampal subfields could be mitigated by maintaining higher CRF in older adulthood.

Abstract Commander is a multiprotein complex that orchestrates endosomal recycling of integral cargo proteins and is essential for normal development. While the structure of this complex has recently been described, how cargo proteins are selected for Commander-mediated recycling remains unclear. Here we identify the mechanism through which the unstructured carboxy-terminal tail of the cargo adaptor sorting nexin-17 (SNX17) directly binds to the Retriever sub-complex of Commander. SNX17 adopts an autoinhibited conformation where its carboxy-terminal tail occupies the cargo binding groove. Competitive cargo binding overcomes this autoinhibition, promoting SNX17 endosomal residency and the release of the tail for Retriever association. Furthermore, our study establishes the central importance of SNX17-Retriever association in the handover of integrin and lipoprotein receptor cargoes into pre-existing endosomal retrieval sub-domains. In describing the principal mechanism of cargo entry into the Commander recycling pathway we provide key insight into the function and regulation of this evolutionary conserved sorting pathway.

Abstract Background Cancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF‐15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF‐15‐mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab‐mediated inactivation of circulating GDF‐15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF‐15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors. Methods Approximately 168 adults with non‐small‐cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF‐15 concentrations will be randomized in a double‐blind, placebo‐controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400 mg) or matching placebo administered subcutaneously every 4 weeks for an initial 12‐week treatment period. This is followed by optional open‐label treatment with ponsegromab of 400 mg administered every 4 weeks for up to 1 year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient‐reported appetite‐related symptoms assessed by Functional Assessment of Anorexia‐Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer‐Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities. Perspective Cancer‐related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF‐15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life. Trial registration ClinicalTrials.gov ID: NCT05546476.

Naringenin (Nar) is a citrus fruit-derived phytoestrogen, a group of dietary compounds produced by a wide variety of plants. Due to structural similarity to 17‐β‐estradiol (E2), phytoestrogens can bind to estrogen receptors (ERs) to exert context-dependent estrogenic and/or anti-estrogenic effects. As such, there are potential health benefits and risks associated with phytoestrogen exposure. To investigate the effects of Nar in breast cancer, based on its activity as a phytoestrogen, we treated MCF-7 ER-positive (ER+) breast cancer cells with Nar (10 µM) and examined transcriptomic changes in MCF-7 cells induced by Nar treatment. Pathway analysis included in our dataset shows upregulation of genes associated with estrogen signaling and epithelial-to-mesenchymal transition in breast cancer cells treated with naringenin.

This paper reports on research conducted by theWits/Tintswalo Community Rehabilitation, Research and Education(CORRE) Programme amongst qualified community rehabilitationworkers (CRWs). The aim was to understand how CRWs see theirrole, successes, supervision support received, problems encounteredand possible solutions.Eighteen qualified CRWs completed a questionnaire, which contained a range of open-ended and semi-structured questions.The findings included their perceived role and successes in theirwork. They were satisfied with the supervision received from theirtherapy supervisors and support from their communities. TheDepartment of Health did not support them as much as did theircommunities. The lack of government assistance for transport wastheir biggest problem: They were not always able to reach far awayclients and spent a lot of time travelling to and from clients everyday. They were also concerned that they were not registerable withthe South African Medical and Dental Council (SAMDC). These findings provided the Northern Province and the CommunityBased Rehabilitation (CBR) manager with information to improveCBR service delivery. A two year diploma course in therapy assistance (community) for CRWs, occupational and physiotherapy assistants has been started.

Background: HER2-targeted therapies have revolutionised the treatment of HER2-positive breast cancer. However, de novo resistance or the emergence of acquired resistance is a persistent clinical problem. Here we report that neratinib, an irreversible pan-HER inhibitor, in combination with the multi-kinase inhibitor dasatinib, currently used to treat certain leukemias, has strong anti-proliferative effects against models of HER2-positive breast cancer that are innately resistant to trastuzumab or have acquired resistance to neratinib. Methods: Neratinib plus dasatinib was examined in a panel of 20 breast cancer cell lines, including HER2-positive, estrogen-receptor-positive, triple negative, and acquired HER2-targeted therapy resistant models. Drug effects on migration and apoptosis induction was evaluated and signaling alterations were determined by reverse phase protein array (RPPA). In vivo efficacy was examined using orthotopically-implanted HCC1954 cells. Results: Synergy was observed in cell lines innately resistant to trastuzumab, models with acquired resistance to neratinib, and in triple negative breast cancer cell lines. Further investigation showed that neratinib plus dasatinib induced apoptosis and inhibited cell migration to a greater degree than either drug alone. RPPA revealed that the combination caused suppression of key survival signaling through EGFR, Akt, and MAPK inhibition. In vivo, neratinib plus dasatinib was well tolerated and had a prolonged anti-tumor effect against HCC1954 xenografts. Conclusions: This study provides a strong pre-clinical rationale for the clinical investigation neratinib and dasatinib in HER2+ breast cancer.

Background: Alterations in gut-brain axis communication pathways and the gut microbiota ecosystem caused by early life stress have been extensively described as critical players in the pathophysiology of stress-induced disorders. However, the extent to which stress-induced gut microbiota alterations manifest in early life and contribute to the sex-specific susceptibility to distinct gut-brain phenotypes in adulthood has yet to be defined. Methods: Male and female Sprague-Dawley rat offspring underwent maternal separation (3h/day from postnatal day 2–12). Faecal samples were collected before weaning for gut microbiota 16S rRNA sequencing and metabolomic analysis. Visceral pain sensitivity and negative valence behaviours were assessed in adulthood using colorectal distension and the forced swim test respectively. Behavioural data were processed in a two-step cluster analysis to identify groupings within the dataset. Multi-omics analysis was carried out to investigate if the microbial signatures following early life stress were already defined according to the membership of the adult behavioural phenotypes. Results: Maternal separation resulted in increased visceral hypersensitivity while showing a trend for a sex-dependent increase in negative valence behaviour in adulthood. The cluster analysis revealed four clusters within the dataset representing distinct pathophysiological domains reminiscent of the behavioural consequences of early-life stress: 1. resilient, 2. pain, 3. immobile and 4. comorbid. The early life gut microbiota of each of these clusters show distinct alterations in terms of diversity, genus level differential abundance, and functional modules. Multi-omic integrations points towards a role for different metabolic pathways underlying each cluster-specific phenotype. Conclusion: Our study is the first to identify distinct phenotypes defined by susceptibility or resilience to gut-brain dysfunction induced by early life stress. The gut microbiota in early life shows sex-dependent alterations in each cluster that precede specific behavioural phenotypes in adulthood. Future research is warranted to determine the causal relationship between early-life stress-induced changes in the gut microbiota and to understand the trajectory leading to the manifestation of different behavioural phenotypes in adulthood.

At the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm3 in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients.

BackgroundMany patients experience persistent symptoms after COVID-19, a syndrome referred to as Long COVID (LC). The goal of this study was to identify novel new or worsening comorbidities self-reported in patients with LC.MethodsPatients diagnosed with LC (n = 732) at the Mayo Long COVID Care Clinic in Rochester, Minnesota and Jacksonville, Florida were sent questionnaires to assess the development of new or worsening comorbidities following COVID-19 compared to patients with SARS-CoV-2 that did not develop LC (controls). Both groups were also asked questions screening for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), generalized joint hypermobility (GJH) and orthostatic intolerance. 247 people with LC (33.7%) and 40 controls (50%) responded to the surveys.ResultsIn this study LC patients averaged 53 years of age and were predominantly White (95%) women (75%). The greatest prevalence of new or worsening comorbidities following SARS-CoV-2 infection in patients with LC vs. controls reported in this study were pain (94.4% vs. 0%, p

Abstract Understanding biotic interactions and how they vary across habitats is important for assessing the vulnerability of communities to climate change. Receding glaciers in high mountain areas can lead to the hydrologic homogenization of streams and reduce habitat heterogeneity, which are predicted to drive declines in regional diversity and imperil endemic species. However, little is known about food web structure in alpine stream habitats, particularly among streams fed by different hydrologic sources (e.g., glaciers or snowfields). We used gut content and stable isotope analyses to characterize food web structure of alpine macroinvertebrate communities in streams fed by glaciers, subterranean ice, and seasonal snowpack in the Teton Range, Wyoming, USA. Specifically, we sought to (1) assess community resource use among streams fed by different hydrologic sources, (2) explore how variability in resource use relates to feeding strategies, and (3) identify which environmental variables influenced resource use within communities. Average taxa diet differed among all hydrologic sources, and food webs in subterranean ice‐fed streams were largely supported by the gold alga Hydrurus. This finding bolsters a hypothesis that streams fed by subterranean ice may provide key habitat for cold‐water species under climate change by maintaining a longer growing season for this high‐quality food resource. While a range of environmental variables associated with hydrologic source (e.g., stream temperature) were related to diet composition, hydrologic source categories explained the most variation in diet composition models. Less variable diets within versus among streams suggest high trophic flexibility, which was further supported by high levels of omnivory. This inherent trophic flexibility may bolster alpine stream communities against future changes in resource availability as the mountain cryosphere fades. Ultimately, our results expand understanding of the habitat requirements for imperiled alpine taxa while empowering predictions of their vulnerability under climate change.

Summary: Diagnosis of respiratory tract infections (RTIs), especially in primary care, is typically made on clinical features and in the absence of quick and reliable diagnostic tests. Even in secondary care, where diagnostic microbiology facilities are available, these tests take 24–48 h to provide an indication of the etiology. This multicentre study used a portable gas chromatography-ion mobility spectrometer (GC-IMS) for the diagnosis of bacterial RTIs. Breath samples taken from 570 participants with 149 clinically validated bacterial and 421 non-bacterial RTIs were analyzed to distinguish bacterial from non-bacterial RTIs. Through the integration of a sparse logistic regression model, we identified a moderate diagnostic accuracy of 0.73 (95% CI 0 · 69, 0 · 77) alongside a sensitivity of 0 · 85 (95% CI 0 · 79, 0 · 91) and a specificity of 0 · 55 (95% CI 0 · 50, 0 · 60). The GC-IMS diagnostic device provides a promising outlook in distinguishing bacterial from non-bacterial RTIs and was also favorably viewed by participants.

Abstract In 2022, a severe outbreak of disease caused by clade 2.3.4.4b Highly Pathogenic Avian Influenza (HPAI) H5N1 virus resulted in unprecedented mortality among wild birds in eastern Canada. Tens of thousands of birds were reported sick or dead, prompting a comprehensive assessment of mortality spanning the breeding season between April 1 and September 30, 2022. Mortality reports were collated from federal, Indigenous, provincial, and municipal agencies, the Canadian Wildlife Health Cooperative, and other nongovernmental organizations, universities, and citizen science platforms. A scenario analysis was conducted to refine mortality estimates, accounting for potential double counts from multiple sources under a range of spatial and temporal overlaps. Correcting for double counting, HPAI is estimated to have caused 40,391 wild bird mortalities in eastern Canada during the spring and summer of 2022; however, this figure underestimates total mortality as it excludes unreported deaths on land and at sea. Seabirds and sea ducks, long‐lived species that are slow to recover from perturbations, accounted for 98.7% of estimated mortalities. Our study provides estimates of bird mortality, with Northern Gannets (Morus bassanus; 25,669), Common Murres (Uria aalge; 8133), and American Common Eiders (Somateria mollissima dresseri; 1894) exhibiting the highest mortality figures. We then compare these mortality estimates with recent population estimates and trends and make an initial assessment of whether biologically meaningful population‐level impacts are possible. Specifically, we focus on the Northern Gannet, a species that has suffered significant global mortality, and two harvested species, Common Murre and American Common Eider, to inform management decisions. Our analysis suggests population‐level impacts in eastern Canada are possible for Northern Gannets and American Common Eiders, but are unlikely for Common Murres. This study demonstrates a comprehensive approach to assessing mortality and underscores the urgent need for further research to understand the broader ecological ramifications of the HPAI outbreak on wild bird populations.

Abstract Persistent post-surgical pain (PPSP) is defined as pain which continues after a surgical operation in a significant form for at least three months (and is not related to pre-existing painful conditions). PPSP is a common, under-recognised, and important clinical problem which affects millions of patients worldwide. Preventative measures which are currently available include the selection of a minimally invasive surgical technique and an aggressive multimodal perioperative analgesic regimen. More recently, a role for the gut microbiota in pain modulation has become increasingly apparent. This study aims to investigate any relationship between the gut microbiota and PPSP. A prospective observational study of 68 female adult patients undergoing surgery for management of breast cancer was carried out. Stool samples from 45 of these patients were obtained to analyse the composition of the gut microbiota. Measures of pain and state-trait anxiety were also taken to investigate further dimensions in any relationship between the gut microbiota and PPSP. At 12 weeks postoperatively, 21 patients (51.2%) did not have any pain and 20 patients (48.8%) reported feeling pain that persisted at that time. Analysis of the gut microbiota revealed significantly lower alpha diversity (using three measures) in those patients reporting severe pain at the 60 min post-operative and the 12 weeks post-operative timepoints. A cluster of taxa represented by Bifidobacterium longum, and Faecalibacterium prausnitzii was closely associated with those individuals reporting no pain at 12 weeks postoperatively, while Megamonas hypermegale, Bacteroides pectinophilus, Ruminococcus bromii, and Roseburia hominis clustered relatively closely in the group of patients fulfilling the criteria for persistent post-operative pain. We report for the first time specific associations between the gut microbiota composition and the presence or absence of PPSP. This may provide further insights into mechanisms behind the role of the gut microbiota in the development of PPSP and could inform future treatment strategies.

Abstract Objectives To investigate differences in students’ career intentions between UK medical schools. Design Cross-sectional, mixed-methods online survey. Setting The primary study included all 44 UK medical schools, with this analysis comprising 42 medical schools. Participants Ten thousand four hundred eighty-six UK medical students. Main outcome measures Career intentions of medical students, focusing on differences between medical schools. Secondary outcomes included variation in medical students’ satisfaction with a prospective career in the NHS, by medical school. Results 2.89% of students intended to leave medicine altogether, with Cambridge Medical School having the highest proportion of such respondents. 32.35% of respondents planned to emigrate for practice, with Ulster medical students being the most likely. Of those intending to emigrate, the University of Central Lancashire saw the highest proportion stating no intentions to return. Cardiff Medical School had the greatest percentage of students intending to assume non-training clinical posts after completing FY2. 35.23% of participating medical students intended to leave the NHS within 2 years of graduating, with Brighton and Sussex holding the highest proportion of these respondents. Only 17.26% were satisfied with the prospect of working in the NHS, with considerable variation nationally; Barts and the London medical students had the highest rates of dissatisfaction. Conclusions This study reveals variability in students’ career sentiment across UK medical schools, emphasising the need for attention to factors influencing these trends. A concerning proportion of students intend to exit the NHS within 2 years of graduating, with substantial variation between institutions. Students’ intentions may be shaped by various factors, including curriculum focus and recruitment practices. It is imperative to re-evaluate these aspects within medical schools, whilst considering the wider national context, to improve student perceptions towards an NHS career. Future research should target underlying causes for these disparities to facilitate improvements to career satisfaction and retention.

Abstract Background Dementia prevalence is predicted to triple to 152 million globally by 2050. Alzheimer’s disease (AD) constitutes 70% of cases. There is an urgent need to identify individuals with preclinical AD, a 10–20-year period of progressive brain pathology without noticeable cognitive symptoms, for targeted risk reduction. Current tests of AD pathology are either too invasive, specialised or expensive for population-level assessments. Cognitive tests are normal in preclinical AD. Emerging evidence demonstrates that movement analysis is sensitive to AD across the disease continuum, including preclinical AD. Our new smartphone test, TapTalk, combines analysis of hand and speech-like movements to detect AD risk. This study aims to [1] determine which combinations of hand-speech movement data most accurately predict preclinical AD [2], determine usability, reliability, and validity of TapTalk in cognitively asymptomatic older adults and [3], prospectively validate TapTalk in older adults who have cognitive symptoms against cognitive tests and clinical diagnoses of Mild Cognitive Impairment and AD dementia. Methods Aim 1 will be addressed in a cross-sectional study of at least 500 cognitively asymptomatic older adults who will complete computerised tests comprising measures of hand motor control (finger tapping) and oro-motor control (syllabic diadochokinesis). So far, 1382 adults, mean (SD) age 66.20 (7.65) years, range 50–92 (72.07% female) have been recruited. Motor measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 to develop an algorithm that classifies preclinical AD risk. Aim 2 comprises three sub-studies in cognitively asymptomatic adults: (i) a cross-sectional study of 30–40 adults to determine the validity of data collection from different types of smartphones, (ii) a prospective cohort study of 50–100 adults ≥ 50 years old to determine usability and test-retest reliability, and (iii) a prospective cohort study of ~1,000 adults ≥ 50 years old to validate against cognitive measures. Aim 3 will be addressed in a cross-sectional study of ~200 participants with cognitive symptoms to validate TapTalk against Montreal Cognitive Assessment and interdisciplinary consensus diagnosis. Discussion This study will establish the precision of TapTalk to identify preclinical AD and estimate risk of cognitive decline. If accurate, this innovative smartphone app will enable low-cost, accessible screening of individuals for AD risk. This will have wide applications in public health initiatives and clinical trials. Trial registration ClinicalTrials.gov identifier: NCT06114914, 29 October 2023. Retrospectively registered.

Abstract The structural performance of polycrystalline alloys is strongly controlled by the characteristics of individual grains and their interactions, motivating this study to understand the dynamic micromechanical response within the microstructure. Here, a high ductility single-phase ferritic steel during uniaxial deformation is explored using three-dimensional X-ray diffraction. Grains well aligned for dislocation slip are shown to possess a wide intergranular stress range, controlled by per-grain dependent hardening activity. Contrariwise, grains orientated poorly for slip have a narrow stress range. A grain neighbourhood effect is observed of statistical significance: the Schmid factor of serial adjoining grains influences the stress state of a grain of interest, whereas parallel neighbours are less influential. This phenomenon is strongest at low plastic strains, with the effect diminishing as grains rotate during plasticity to eliminate any orientation dependent load shedding. The ability of the ferrite to eliminate such neighbourhood interactions is considered key to the high ductility possessed by these materials.

Abstract Skeletal development depends on coordinated angiogenesis and osteogenesis. Bone morphogenetic proteins direct bone formation in part by activating SMAD1/5 signaling in osteoblasts. However, the role of SMAD1/5 in skeletal endothelium is unknown. Here, we found that endothelial cell-conditional SMAD1/5 depletion in juvenile mice caused metaphyseal and diaphyseal hypervascularity, resulting in altered trabecular and cortical bone formation. SMAD1/5 depletion induced excessive sprouting and disrupting the morphology of the metaphyseal vessels, with impaired anastomotic loop formation at the chondro-osseous junction. Endothelial SMAD1/5 depletion impaired growth plate resorption and, upon long-term depletion, abrogated osteoprogenitor recruitment to the primary spongiosa. Finally, in the diaphysis, endothelial SMAD1/5 activity was necessary to maintain the sinusoidal phenotype, with SMAD1/5 depletion inducing formation of large vascular loops and elevated vascular permeability. Together, endothelial SMAD1/5 activity sustains skeletal vascular morphogenesis and function and coordinates growth plate remodeling and osteoprogenitor recruitment dynamics in juvenile mouse bone.

Abstract Objective Female representation in the field of otolaryngology is lacking. Residency is the first point at which medical school graduates specialize in a chosen field and thus represents an opportunity to recruit and train more female otolaryngologists. This study sought to identify program factors associated with greater female representation among resident physicians. Methods Departmental websites of all 124 otolaryngology residency programs in the United States and Puerto Rico were examined for a list of residents. For programs with a resident roster available, the genders of residents, faculty, program directors, and chairpersons were recorded. Location and city population for each program was also recorded, as was female resident representation. Programs were compared using Pearson Chi‐squared univariate tests. Results 1,632 residents and 2,605 faculty were included in the analysis of 109 programs. The median female resident representation was 40%. Programs with larger faculty sizes, more female faculty, and urban location were associated with an above‐median female resident representation. Programs with a larger residency cohort approached significance regarding above‐median female resident representation. Higher female faculty representation, program director gender, chairperson gender, and US region were not associated with variation in female resident representation. Conclusions Greater female otolaryngology residency representation was associated with programs having an urban location and greater numbers of female and total faculty. It was also likely that a larger resident cohort size may affect female resident representation. The proportions of female faculty, program director, and chairperson gender, as well as the US region, were not associated with variation in female resident gender representation.

From >1000 orbits of HST imaging, we present deep homogeneous resolved star color–magnitude diagrams that reach the oldest main-sequence turnoff and uniformly measured star formation histories (SFHs) of 36 dwarf galaxies (−6 ≥ M _V ≥ −17) associated with the M31 halo, and for 10 additional fields in M31, M33, and the Giant Stellar Stream. From our SFHs, we find: (i) The median stellar age and quenching epoch of M31 satellites correlate with galaxy luminosity and galactocentric distance. Satellite luminosity and present-day distance from M31 predict the satellite quenching epoch to within 1.8 Gyr at all epochs. This tight relationship highlights the fundamental connection between satellite halo mass, environmental history, and star formation duration. (ii) There is no difference between the median SFH of galaxies on and off the great plane of Andromeda satellites. (iii) ~50% of our M31 satellites show prominent ancient star formation (>12 Gyr ago) followed by delayed quenching (8–10 Gyr ago), which is not commonly observed among the MW satellites. (iv) A comparison with TNG50 and FIRE-2 simulated satellite dwarfs around M31-like hosts shows that some of these trends (dependence of SFH on satellite luminosity) are reproduced in the simulations while others (dependence of SFH on galactocentric distance, presence of the delayed-quenching population) are weaker or absent. We provide all photometric catalogs and SFHs as High-Level Science Products on MAST.

We report the discovery and spectroscopic confirmation of an ultra-faint Milky Way satellite in the constellation of Leo. This system was discovered as a spatial overdensity of resolved stars observed with Dark Energy Camera (DECam) data from an early version of the third data release of the DECam Local Volume Exploration (or DELVE) survey. The low luminosity ( ${M}_{V}=-3.5{6}_{-0.37}^{+0.47}$ ; ${L}_{V}=230{0}_{-700}^{+1200}{L}_{\odot }$ ), large size ( ${R}_{1/2}=9{0}_{-30}^{+30}$ pc), and large heliocentric distance ( $D=11{1}_{-6}^{+9}$ kpc) are all consistent with the population of ultra-faint dwarf galaxies (UFDs). Using Keck/DEIMOS observations of the system, we were able to spectroscopically confirm nine member stars, while measuring a tentative mass-to-light ratio of $70{0}_{-500}^{+1400}{M}_{\odot }/{L}_{\odot }$ and a nonzero metallicity dispersion of ${\sigma }_{[\mathrm{Fe}/{\rm{H}}]}=0.1{9}_{-0.11}^{+0.14}$ , further confirming Leo VI’s identity as a UFD. While the system has a highly elliptical shape, $\epsilon =0.5{4}_{-0.29}^{+0.19}$ , we do not find any conclusive evidence that it is tidally disrupting. Moreover, despite the apparent on-sky proximity of Leo VI to members of the proposed Crater-Leo infall group, its smaller heliocentric distance and inconsistent position in energy–angular momentum space make it unlikely that Leo VI is part of the proposed infall group.