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Climate change threatens our ability to grow food for an ever-increasing population. There is a need for high-quality soil moisture predictions in under-monitored regions like Africa. However, it is unclear if soil moisture processes are globally similar enough to allow our models trained on available in situ data to maintain accuracy in unmonitored regions. We present a multitask long short-term memory (LSTM) model that learns simultaneously from global satellite-based data and in situ soil moisture data. This model is evaluated in both random spatial holdout mode and continental holdout mode (trained on some continents, tested on a different one). The model compared favorably to current land surface models, satellite products, and a candidate machine learning model, reaching a global median correlation of 0.792 for the random spatial holdout test. It behaved surprisingly well in Africa and Australia, showing high correlation even when we excluded their sites from the training set, but it performed relatively poorly in Alaska where rapid changes are occurring. In all but one continent (Asia), the multitask model in the worst-case scenario test performed better than the soil moisture active passive (SMAP) 9 km product. Factorial analysis has shown that the LSTM model's accuracy varies with terrain aspect, resulting in lower performance for dry and south-facing slopes or wet and north-facing slopes. This knowledge helps us apply the model while understanding its limitations. This model is being integrated into an operational agricultural assistance application which currently provides information to 13 million African farmers.

Abstract Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder due to the deficient activity of the acid beta-glucosidase (GCase) enzyme, resulting in the progressive lysosomal accumulation of glucosylceramide (GlcCer) and its deacylated derivate, glucosylsphingosine (GlcSph). GCase is encoded by the GBA1 gene, located on chromosome 1q21 16 kb upstream from a highly homologous pseudogene. To date, more than 400 GBA1 pathogenic variants have been reported, many of them derived from recombination events between the gene and the pseudogene. In the last years, the increased access to new technologies has led to an exponential growth in the number of diagnostic laboratories offering GD testing. However, both biochemical and genetic diagnosis of GD are challenging and to date no specific evidence-based guidelines for the laboratory diagnosis of GD have been published. The objective of the guidelines presented here is to provide evidence-based recommendations for the technical implementation and interpretation of biochemical and genetic testing for the diagnosis of GD to ensure a timely and accurate diagnosis for patients with GD worldwide. The guidelines have been developed by members of the Diagnostic Working group of the International Working Group of Gaucher Disease (IWGGD), a non-profit network established to promote clinical and basic research into GD for the ultimate purpose of improving the lives of patients with this disease. One of the goals of the IWGGD is to support equitable access to diagnosis of GD and to standardize procedures to ensure an accurate diagnosis. Therefore, a guideline development group consisting of biochemists and geneticists working in the field of GD diagnosis was established and a list of topics to be discussed was selected. In these guidelines, twenty recommendations are provided based on information gathered through a systematic review of the literature and two different diagnostic algorithms are presented, considering the geographical differences in the access to diagnostic services. Besides, several gaps in the current diagnostic workflow were identified and actions to fulfill them were taken within the IWGGD. We believe that the implementation of recommendations provided in these guidelines will promote an equitable, timely and accurate diagnosis for patients with GD worldwide.

The African continent is probably the one with the lowest density of hydrometric stations currently measuring river discharge despite the fact that the number of operating stations was quite important until the 1970s. This new African Database of Hydrometric Indices (ADHI) provides a wide range of hydrometric indices and hydrological signatures computed from different sources of data after a quality control. It includes 1466 stations with at least 10 years of daily discharge data over the period 1950–2018. The average record length is 33 years, and 131 stations have complete records over 50 years. With this new dataset spanning most climatic regions of the African continent, several hydrometric indices have been computed, representing mean flow characteristics and extremes (low flows and floods), and are accessible to the scientific community. The database will be updated on a regular basis to include more hydrometric stations and longer time series of river discharge. The ADHI is available for download at: https://doi.org/10.23708/LXGXQ9 (Tramblay and Rouché, 2020).

Water availability is one of the major societal issues facing the world. The ability to understand and quantify the impact of key hydrological processes, on the availability of water resources, is therefore integral to ensuring equitable and sustainable resource management. Channel transmission losses are an under-researched hydrological process that affects resource availability in many semi-arid regions such as the Limpopo River Basin in southern Africa, where the loss processes amount to approximately 30 % of the water balance. To improve the understanding of these loss processes and test the capability of modelling routines, three approaches using the Pitman model are applied to selected alluvial aquifer environments. The three approaches are an explicit transmission loss function, the use of a wetland function to represent channel-floodplain storage exchanges and the use of a dummy reservoir to represent floodplain storage and evapotranspiration losses. Results indicate that all three approaches are able to simulate channel transmission losses with differing impacts on the regional flows. A determination of which method best represents the channel transmission losses process requires further testing in a study area that has reliable observed historical records.

The estimation of soil loss and sediment transport is important for effective management of catchments. A model for semi-arid catchments in southern Africa has been developed; however, simplification of the model parameters and further testing are required. Soil loss is calculated through the Modified Universal Soil Loss Equation (MUSLE). The aims of the current study were to: (1) regionalise the MUSLE erodibility factors and; (2) perform a sensitivity analysis and validate the soil loss outputs against independently-estimated measures. The regionalisation was developed using Geographic Information Systems (GIS) coverages. The model was applied to a high erosion semi-arid region in the Eastern Cape, South Africa. Sensitivity analysis indicated model outputs to be more sensitive to the vegetation cover factor. The simulated soil loss estimates of 40 t ha−1 yr−1 were within the range of estimates by previous studies. The outcome of the present research is a framework for parameter estimation for the MUSLE through regionalisation. This is part of the ongoing development of a model which can estimate soil loss and sediment delivery at broad spatial and temporal scales.

Long-term in vitro models for hepatitis B virus (HBV) infection are important to understand this infection, but are lacking. Here the authors develop a microfluidic primary human hepatocyte organoid culture system that can be maintained over 40 days and recapitulates all of the steps of the HBV life cycle.

Abstract Background This post hoc subanalysis examined outcomes in adult patients with Morquio A (mucopolysaccharidosis IVA) who received enzyme replacement therapy (ERT) with elosulfase alfa over a 120-weeks period. Patients ≥18 years of age evaluated in an open-label, long-term extension study of elosulfase alfa (modified per protocol [MPP], n = 32; intent-to-treat [ITT], n = 37; MOR-005; NCT01415427) were compared with the ≥18-year-old untreated population with 2-years follow-up from a Morquio A natural history study (n = 10; MorCAP; NCT00787995). The MOR-005 MPP population excluded patients who underwent orthopedic surgical procedures or were noncompliant with study protocol (defined as missing ≥20% of ERT infusions). No MorCAP patients underwent orthopedic surgical procedures during the relevant time period. Endurance was assessed by the 6-min walk test (6MWT) and 3-min stair climb test (3MSCT). Activities of daily living (ADLs) were assessed by the MPS Health Assessment Questionnaire (MPS HAQ). Results Least squares (LS) mean (SE) 6MWT distances increased by 34.9 (11.7) m (MPP) and 30.5 (10.8) m (ITT) by week 120; LS mean (SE) change in 3MSCT at week 120 was 6.7 (1.8) stairs/min (MPP) and 5.9 (1.7) stairs/min (ITT). MorCAP patients showed no improvement in 6MWT distance or 3MSCT over a similar period of time. Pulmonary function measures remained unchanged in both MOR-005 and MorCAP adults. All MPS HAQ domain scores improved in MOR-005 adults, whereas MorCAP adults had unchanged caregiver assistance and mobility outcomes and worsened self-care outcomes. Conclusions Long-term ERT in adult patients with Morquio A was associated with increased endurance and improvement in performance of ADLs. Trial registration Trial Registration NCT01415427 . Name of registry: Long-Term Efficacy and Safety Extension Study of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome). Registered 8 August 2011, retrospectively registered.

Abstract Exercise capacity is a strong independent predictor of cardiovascular and all-cause mortality. The utilization of well-established submaximal tests of exercise capacity such as the 6-min walk test (6MWT), 3-min step test (3MST) and 10-chair rise test (10CRT) in the community would improve patient care but requires remote monitoring technology. Consumer grade smartwatches provide such an opportunity, however, their accuracy in measuring physiological responses to these tests is unclear. The aim of this study was to determine the accuracy of consumer grade smartwatches in assessing exercise capacity to develop a framework for remote, unsupervised testing. 16 healthy adults (7 male (44%), age median 27 [interquartile range (IQR) 26,29] years) performed 6MWTs using two protocols: (1) standard—straight 30 m laps (6MWT-standard) and 2) continuous lap—circular 240 m laps around a park (6MWT-continuous lap), 3MSTs and 10CRTs. Each one of these four tests was performed three times across two clinic visits. Each participant was fitted with a Garmin Vivoactive4 and Fitbit Sense smartwatch to measure three parameters: distance, step counts and heart rate (HR) response. Reference measures were a meter-wheel, hand tally counter and ECG, respectively. Mean HR was measured at rest, peak exercise and recovery. Agreement was measured using Bland–Altman analysis for repeated measures and summarized as median absolute percentage errors (MAPE). Distance during 6MWT-continuous lap had better agreement than during 6MWT-standard for both Garmin (MAPE: 6.4% [3.0, 10.4%] versus 20.1% [13.9, 28.4%], p

Abstract Aims Parameters derived from reservoir‐excess pressure analysis have been demonstrated to predict cardiovascular events. Thus, altered reservoir‐excess pressure parameters could have a detrimental effect on highly‐perfused organs like the heart. We aimed to cross‐sectionally determine whether reservoir‐excess pressure parameters were associated with N‐terminal pro‐brain‐type natriuretic peptide (NT‐proBNP) in older adults. Methods We studied 868 older adults with diverse cardiovascular risk. Reservoir‐excess pressure parameters were obtained through radial artery tonometry including reservoir pressure integral, peak reservoir pressure, excess pressure integral (INTXSP), systolic rate constant (SRC) and diastolic rate constant (DRC). Plasma levels of NT‐proBNP, as a biomarker of cardiac overload, were analysed by the Proximity Extension Assay technology. Results Multivariable linear regression analyses revealed that all reservoir‐excess pressure parameters studied were associated with NT‐proBNP after adjusting for age and sex. After further adjustments for conventional cardiovascular risk factors, INTXSP [β = 0.191 (95% confidence interval, CI: 0.099, 0.283), P

No abstract available.

The cause for severe, recurrent lower gastrointestinal (LGI) bleeding in children can usually be diagnosed readily by means of the commonly used investigative/diagnostic techniques such as colonoscopy, laparoscopy ± laparotomy. Occasionally less commonly used investigations may be necessary to look for more elusive causes of LGI bleeding such as capsule endoscopy, angiography, technetium-99m (99m Tc)-labeled red blood cell (RBC) scintigraphy, cross-sectional imaging such as CT/MRI (including angiography) and laparotomy combined with on-table small bowel enteroscopy. We report a case of severe, recurrent LGI bleeding that had occurred over several years, where the cause remained elusive despite numerous investigations and interventions. The etiology of this was eventually found to be a gastric duplication cyst infiltrating into adjacent transverse colon and causing bleeding from peptic ulceration in the colon. The process by which this diagnosis was made and the lessons learned are discussed.

Abstract Wave intensity and wave speed are measures used to assess the dynamic properties of the arteries and travelling waves within the circulation. Wave intensity and wave speed measured in the carotid artery have the potential to provide hemodynamic and biophysical insights that can advance our understanding of the physiology of cerebral circulation. However, whilst studies have been performed in different patient cohorts exploring different methodological implementations of wave intensity analysis (WIA), to date little work has been done to unify wave measures or provide reference ranges on which to build the field of research and inform clinical practice. This review thus focuses on wave speed and wave intensity in the carotid artery in man with the aim to summarise the current knowledge of the field. From this review, the different methods of measurement and the disparity of the reported values currently hinder efforts to construct reference ranges for a comparator or intervention to be assessed.

The occurrence of linear- and cyclic-volatile methyl siloxanes (lVMSs and cVMSs, respectively) in various indoor environments, occupational and domestic, in Italy and in the United Kingdom was studied. The results show that the cVMSs are the most abundant, detected in average concentrations that in some cases were as high as 170 μg m−3. Our study highlights the differences that can be observed between various indoor environments (e.g. domestic like bathrooms, bedrooms, or occupational) and between two countries. In most cases, the concentrations found in the UK are higher than in the respective indoor environments in Italy. The assessment of exposure to these two countries for adults and children revealed significant differences both not only in the levels of exposure, but also in the patterns. In Italy, the biggest part of the exposure to VMSs takes place domestically, whereas in the UK, it is observed for occupational environments.Additionally, the compound specific isotopic analysis was employed as a source identification technique. The results are promising mainly for D5 that occurs in higher concentrations, but not for the less abundant lVMSs and cVMSs. Keywords: Indoor air, Siloxanes, D4, D5, Exposure assessment, CSIA

Seaweed aquaculture is gaining traction globally as a solution to many climate issues. However, seaweeds themselves are also under threat of anthropogenically driven climate change. Here, we summarize climate-related challenges to the seaweed aquaculture industry, with a focus on the developing trade in the North Atlantic. Specifically, we summarize three main challenges: i) abiotic change; ii) extreme events; and iii) disease & herbivory. Abiotic change includes negative effects of ocean warming and acidification, as well as altered seasonality due to ocean warming. This can lower biomass yield and change biochemical composition of the seaweeds. Extreme events can cause considerable damage and loss to seaweed farms, particularly due to marine heatwaves, storms and freshwater inputs. Seaweed diseases have a higher chance of proliferating under environmentally stressful conditions such as ocean warming and decreased salinity. Herbivory causes loss of biomass but is not well researched in relation to seaweed aquaculture in the North Atlantic. Despite challenges, opportunities exist to improve resilience to climate change, summarized in three sections: i) future proof site selection; ii) advances in breeding and microbiome manipulation; and iii) restorative aquaculture. We present a case study where we use predictive modelling to illustrate suitable habitat for seaweed cultivation in the North Atlantic under future ocean warming. Notably, there was a large loss of suitable habitat for cultivating Alaria esculenta and Laminaria digitata. We show how selection and priming and microbe inoculates may be a cost-effective and scalable solution to improve disease- and thermal tolerance. Co-cultivation of seaweeds may increase both yield and biodiversity co-benefits. Finally, we show that aquaculture and restoration can benefit from collaborating on nursery techniques and push for improved legislation.

Urban landscapes are expanding, increasing the wildland-urban interface and leading to more frequent wildlife-human conflict. This publication discusses how to reduce conflict venomous snakes. We first discuss the ecological benefits of these species and then provide suggestions on how to limit conflicts with them. The overarching goal of this publication is to increase the likelihood of coexistence between humans and venomous snakes.

Aim: The management of cardiorespiratory arrest in a diving bell presents multiple clinical, technical, and environmental considerations that standard resuscitation algorithms do not address, and no situation-specific algorithm exists. The development and testing of an algorithm to guide the management of cardiorespiratory arrest in a bell is described. Methods: An iterative approach to algorithm development was used. Phase 1 involved a small multidisciplinary group and took place in a simulation centre and a decommissioned diving bell. The algorithm was then refined in a purpose-build simulation complex with repeated simulation by a group of divers, and with input from industry experts. ALS principles were followed unless contextual or technical factors necessitated deviation. Results: Clinical and technical aspects of the resuscitation are addressed. Key priorities that conflict with standard ALS principles are: prioritisation of rescue breaths; use of mechanical CPR when available; and the provision of CPR with the casualty in a seated position where necessary. Conclusion: This is the first algorithm to guide the delivery of resuscitation in a diving bell. It incorporates adapted ALS principles and available data concerning compression technique effectiveness, and was informed by industry and clinical expertise. It provides guiding principles that can be adapted to setting-specific needs, and we would encourage its industry-wide international adoption.

Summary: Background: It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID. Methods: Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo. Findings: Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53–0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID. Interpretation: Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID. Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Formation of new aerosol particles by nucleation and growth is a significant source of aerosols in the atmosphere. New particle formation events usually take place during daytime, but in some locations they have been observed also at night. In the present study we have combined chamber experiments, quantum chemical calculations and aerosol dynamics models to study nocturnal new particle formation. All our approaches demonstrate, in a consistent manner, that the oxidation products of monoterpenes play an important role in nocturnal nucleation events. By varying the conditions in our chamber experiments, we were able to reproduce the very different types of nocturnal events observed earlier in the atmosphere. The exact strength, duration and shape of the events appears to be sensitive to the type and concentration of reacting monoterpenes, as well as the extent to which the monoterpenes are exposed to ozone and potentially other atmospheric oxidants.

Biogenic aerosol formation is likely to contribute significantly to the global aerosol load. In recent years, new-particle formation has been observed in various ecosystems around the world but hardly any measurements have taken place in the terrestrial Southern Hemisphere. Here, we report the first results of atmospheric ion and charged particle concentrations as well as of new-particle formation in a Eucalypt forest in Tumbarumba, South-East Australia, from July 2005 to October 2006. The measurements were carried out with an Air Ion Spectrometer (AIS) with a size range from 0.34 to 40 nm. The Eucalypt forest was a very strong source of new aerosol particles. Daytime aerosol formation took place on 52% of days with acceptable data, which is 2–3 times as often as in the Nordic boreal zone. Average growth rates for negative/positive 1.5–3 nm particles during these formation events were 2.89/2.68 nmh−1, respectively; for 3-7 nm particles 4.26/4.03, and for 7–20 nm particles 8.90/7.58 nmh−1, respectively. The growth rates for large ions were highest when the air was coming from the native forest which suggests that the Eucalypts were a strong source of condensable vapours. Average concentrations of cluster ions (0.34–1.8 nm) were 2400/1700 cm−3 for negative/positive ions, very high compared to most other measurements around the world. One reason behind these high concentrations could be the strong radon efflux from the soils around the Tumbarumba field site. Furthermore, comparison between night-time and daytime concentrations supported the view that cluster ions are produced close to the surface within the boundary layer also at night but that large ions are mostly produced in daytime. Finally, a previously unreported phenomenon, nocturnal aerosol formation, appeared in 32% of the analysed nights but was clustered almost entirely within six months from summer to autumn in 2006. From January to May, nocturnal formation was 2.5 times as frequent as daytime formation. Therefore, it appears that in summer and autumn, nocturnal production was the major mechanism for aerosol formation in Tumbarumba.

Abstract Background In addition to the other uses for macroalgae, since the 1970s, there has been interest in using macroalgae as a source of biofuels, due to the high rates of productivity and intrinsic advantages over other biofuel crops such as not requiring land use or significant freshwater input. A wide range of conversion processes exist but anaerobic digestion was one of the first demonstrated and is still a widely proposed conversion pathway. To be economically viable and scalable within Europe, the industry will need to be based on a small number of fast growing, high-yielding European macroalgae species. There is a wide body of scientific work on the conversion of seaweeds to biofuel via anaerobic digestion. Main text These studies demonstrate that the efficiency of this conversion pathway is highly variable between species, processing techniques, composition and digestor conditions. In this paper, we review this body of work specifically linking it to candidate species for European macroalgae bio-energy cultivation with the aim to promote the future development of the European macroalgal cultivation sector and allow for a better alignment with the requirements for biofuel production from macroalgae. Conclusions Overall, anaerobic digestion of seaweed offers opportunities for large-scale energy production which avoids some of the issues that have faced previous generations of biofuels, but there are a number of key challenges to overcome to ensure wider adoption and economic viability. (1) Optimising the biomass production to ensure an economic and uniform feedstock with the composition optimised to increase desirable characteristics such as sugar content and the carbon and nitrogen ratio and to reduce inhibitory factors such as halogenated secondary metabolites, sulphur and heavy metals. (2) Improving conversion rates through co-digestion, pre-treatments and tailored microbial communities, using scalable and economically feasible technology. (3) Developing tailored microbial communities capable of utilising the diverse polysaccharides in seaweed feedstock and being tolerant of the saline conditions associated with them. Addressing these issues will deliver significant benefits towards the development of a bio-energy industry based on the anaerobic digestion of cultured seaweeds.

Abstract Background Although APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy). Methods Combining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent Revised [SABRE], and UK Biobank) and one younger age cohort (Avon Longitudinal Study of Parents and Children [ALSPAC]), we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional metrics by echocardiography and cardiovascular magnetic resonance (CMR). Results Compared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac phenotypes in terms of LV ejection fraction, E/e’, posterior wall and interventricular septal thickness, and LV mass. However, they had improved myocardial performance resulting in greater LV stroke volume generation per 1 mL of myocardium (higher myocardial contraction fraction). In NSHD (n = 1467) and SABRE (n = 1187), ε4 carriers had a 4% higher MCF (95% CI 1–7%, p = 0.016) using echocardiography. Using CMR data, in UK Biobank (n = 32,972), ε4 carriers had a 1% higher MCF 95% (CI 0–1%, p = 0.020) with a dose-response relationship based on the number of ε4 alleles. In addition, UK Biobank ε4 carriers also had more favorable radial and longitudinal strain rates compared to non APOE ε4 carriers. In ALSPAC (n = 1397), APOE ε4 carriers aged

Background: Cognitive function has an important role in determining the quality of life of older adults. Cardiovascular disease (CVD) is common in older people and may compromise cognitive performance; however, the extent to which this is related to carotid atherosclerosis is unclear. Aim: We investigated associations between carotid atherosclerosis and cognitive function and neuroimaging markers of brain health in a UK multi-ethnic community-based sample including older people of European, South Asian, and African-Caribbean ethnicity. Methods: Carotid plaques and intima-media thickness (cIMT) were assessed using ultrasound in 985 people (mean age 73.2y, 56 % male). Associations of carotid atherosclerosis with cognitive function (memory, executive function, language and CSI-D, a global measure of cognitive state) and neuroimaging measures (total brain volume, hippocampal volume, white matter (WM) lesion volume and coalescence score) were analysed using regression analyses, with and without adjustment for potential confounders using two models: 1) adjustment for age, sex, and ethnicity; 2) model 1 plus education, physical activity category, body mass index, hypertension, diabetes, total and high density lipoprotein cholesterol, atrial fibrillation, smoking, previous CVD, alcohol consumption, and presence of chronic kidney disease. Results: People with carotid plaque or higher cIMT had lower CSI-D score, poorer memory poorer executive function and higher WM lesion volume and coalescence. Language was poorer in people with plaque but was not correlated with cIMT. Associations with plaque were preserved after full adjustment (model 2) but relationships for cIMT were attenuated. Associations with other plaque characteristics were generally unconvincing after adjustment. Conclusions: This multi-ethnic cohort study provides evidence that presence of carotid plaque, is associated with poorer cognitive function and brain health.

Repressor element-1 silencing transcription factor (REST) is a candidate modulator of gene expression during status epilepticus in the rodent. In such models, full-length REST and the truncated REST4 variant are induced and can potentially direct differential gene expression patterns. We have addressed the regulation of these REST variants in rodent hippocampal seizure models and correlated this with expression of the proconvulsant, substance P encoding, PPT-A gene. REST and REST4 were differentially regulated following kainic acid stimulus both in in vitro and in vivo models. REST4 was more tightly regulated than REST in both models and its transient expression correlated with that of the differential regulation of PPT-A. Consistent with this, overexpression of a truncated REST protein (HZ4, lacking the C-terminal repression domain) increased expression of the endogenous PPT-A gene. Similarly the proximal PPT-A promoter reporter gene construct was differentially regulated by the distinct REST isoforms in hippocampal cells with HZ4 being the major inducer of increased reporter expression. Furthermore, REST and REST4 proteins were differentially expressed and compartmentalized within rat hippocampal cells in vitro following noxious stimuli. This differential localization of the REST isoforms was confirmed in the CA1 region following perforant path and kainic acid induction of status epilepticus in vivo. We propose that the interplay between REST and REST4 alter the expression of proconvulsant genes, as exemplified by the PPT-A gene, and may therefore regulate the progression of epileptogenesis.

Introduction Coaches play a major role in developing movement in their performers, especially at grassroots levels. However, there are significant knowledge gaps amongst grassroots coaches and physical education (PE) teachers regarding movement competency and injury prevention programs. This study aimed to explore the effectiveness of knowledge gain, adoption and implementation following a youth injury prevention workshop for grassroots coaches and PE teachers.Methods 56 grassroots coaches and PE teachers completed a validated questionnaire exploring use, knowledge, attitude towards and confidence to deliver youth movement competency training before and after an online workshop. Bayesian Wilcoxon signed-rank tests were used to assess the knowledge, attitude, and confidence to deliver an injury prevention programme following the workshop. For all the Bayesian inference tests run, the Bayesian factor (BF10) was interpreted using the evidence categories ranging from extreme evidence (BF10 > 100) to anecdotical evidence (BF10 < 1).Results Post-workshop there was a 34% increase in respondents indicating that they had greater knowledge of injury prevention issues (55% pre-workshop vs 89% post-workshop) with statistically positive and moderate effects (BF10 > 100 [extreme evidence]). There was also a 25% increase in respondents indicating that they had a more sympathetic attitude towards injury prevention (67% sympathetic pre-workshop vs 93% sympathetic post-workshop) with statistically moderate effects (BF10 = 87.4 [very strong evidence]). A 19% increase in attendees’ confidence to deliver an injury prevention programme was observed (69% high pre-workshop vs. 89% high post-workshop) with statistically moderate effects (BF10 = 85.9 [very strong evidence]). 100% of participants indicated an intent to adopt the injury prevention programme.Conclusions An online workshop increased knowledge and confidence in grassroots coaches and PE teachers to deliver a youth injury prevention programme. Knowledge gained from training and upskilling created a positive attitude and confidence to deliver movement competency into coaching. Appropriate resources need to be developed and delivered in an accessible way to grassroots coaches and PE teachers via workshops and should be included in governing body coaching awards or as continuing professional development for youth coaches and PE teachers.

In the present paper, concept of a periodic structure is used to study the characteristics of the natural frequencies of a complete unstiffened cylindrical shell. A segment of the shell between two consecutive nodal points is chosen to be a periodic structural element. The present effort is to modify Mead and Bardell's approach to study the free vibration characteristics of unstiffened cylindrical shell. The Love-Timoshenko formulation for the strain energy is used in conjunction with Hamilton's principle to compute the natural propagation constants for two shell geometries and different circumferential nodal patterns employing Floquet's principle. The natural frequencies were obtained using Sengupta's method and were compared with those obtained from classical Arnold-Warburton's method. The results from the wave propagation method were found to compare identically with the classical methods, since both the methods lead to the exact solution of the same problem. Thus consideration of the shell segment between two consecutive nodal points as a periodic structure is validated. The variations of the phase constants at the lower bounding frequency for the first propagation band for different nodal patterns have been computed. The method is highly computationally efficient.

BackgroundNear-infrared spectroscopy (NIRS) provides a non-invasive, cost-effective method for assessing skeletal muscle oxidative capacity when combined with a short exercise protocol and arterial occlusions. However, the impact of different exercise protocols and reproducibility of the method in non-athletic adults have not previously been assessed.MethodsYoung, non-athletic adults (YA) were invited to perform a short duration, fast frequency contraction (SF) exercise protocol and a long duration slow frequency (LS) contraction protocol, combined with NIRS measurements and arterial occlusions to assess skeletal muscle oxidative capacity. YA and older non-athletic adults (OA; >65 years old) were invited to perform the SF exercise protocol twice to assess the reproducibility of this oxidative capacity measurement.ResultsWe included 25 participants (14 male (56%), age range: 18–86 years) in the analyses. There was a strong positive correlation and good agreement between time constants derived following the SF and LS exercise protocols (Lin’s concordance correlation coefficient: 0.69, p-value < 0.001 mean bias [LoA]: −3.2 [−31.0, 24.4] seconds. There was a strong positive correlation and good agreement between time constants derived from the SF exercise protocol in the YA & OA group (Lin’s concordance correlation coefficient: 0.63, p-value < 0.001; mean bias [LoA] −6.4 [−34.0, 21.3] seconds).ConclusionThese data provide evidence to suggest that NIRS is a reliable in vivo method for the assessment of skeletal muscle oxidative capacity irrespective of exercise protocol duration or muscle contraction frequency. NIRS-measured oxidative capacity via the SF exercise protocol was reproducible in non-athletic adults with a wide range in age.

Abstract Aim There has been significant progress made in developing novel targeted therapies in the neoadjuvant setting for non‐metastatic HER2‐positive breast cancer, which may be used in combination with conventional chemotherapy to optimise pathological responses at surgery. However, these therapies, particularly the chemotherapeutic components, may portend significant and long‐lasting toxicity. Hence, de‐escalation of treatment intensity has been an area of interest and was evaluated in the phase II NeoSphere study. Herein, we report the real‐world pathological and survival outcomes from neoadjuvant taxane and dual HER2 blockade recorded at our centre. Methods This was a retrospective cohort study of patients receiving neoadjuvant pertuzumab, trastuzumab and taxane chemotherapy for non‐metastatic HER2‐positive breast cancer at a single centre in Sydney, Australia. We collected data pertaining to baseline demographic characteristics, pathological response rates, post‐surgical prescribing patterns and also undertook survival analyses for invasive disease‐free survival (iDFS) as well as exploratory analyses for correlations between pre‐specified clinicopathologic factors and pathological response at surgery. Results Our population was largely similar at baseline to the NeoSphere study. 71 patients were included in the final analysis. 61% achieved a pathological complete response (pCR). Three patients received conventional chemotherapy in the adjuvant setting. 92% of included patients were alive and disease‐free at 3 years of follow‐up. Only 3 events of recurrence or death were recorded at a median follow‐up of 32 months. No significant difference in iDFS was noted between patients achieving pCR and those with residual disease at surgery. Conclusion This study demonstrates that de‐escalated adjuvant treatment for HER2‐positive early breast cancer achieved favourable pathological and long‐term outcomes comparable to large trials, some utilising more intensive chemotherapeutic components.

Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known.Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors.Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health.Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86).Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need.Trail registration number ISRCTN10980107.

No abstract available.

Abstract Background Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person’s risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46—a multi-phase longitudinal observational study—are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. Methods/Design Phase 1 of Insight 46 (2015–2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018–2021) and phase 3 (2021–ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. Discussion The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

BackgroundTelehealth (telemedicine and telepharmacy) services increase access to patient services and ensure continuity of care. However, few studies have assessed factors that influence patients’ willingness to use telehealth services, and we sought to investigate this. ObjectiveThis study aims to examine respondents’ (aged between 45 and 75 years) willingness to use telehealth services (telepharmacy and telemedicine) and the correlates of the willingness to use telehealth services. MethodsWe administered a cross-sectional national survey of 1045 noninstitutionalized US adults aged between 45 and 75 years in March and April 2021. Multiple logistic regression analyses were used to identify demographic and health service use correlates of self-reported willingness to use telehealth services. ResultsOverall willingness to use telemedicine was high (674/1045, 64.5%). Adults aged 55 years and older were less willing to use telemedicine (aged between 55 and 64 years: odds ratio [OR] 0.61, 95% CI 0.42-0.86; aged 65 years or older: OR 0.33, 95% CI 0.22-0.49) than those younger than 55 years. Those with a regular provider (OR 1.01, 95% CI 1-1.02) and long travel times (OR 1.75, 95% CI 1.03-2.98) were more willing to use telemedicine compared to those without a regular provider and had shorter travel times, respectively. Willingness to use telemedicine services increased from 64.5% (674/1045) to 83% (867/1045) if the service was low-cost or insurance-covered, was with their existing health care provider, or was easy-to-use. Overall willingness to use telepharmacy was 76.7% (801/1045). Adults aged older than 55 years were less willing to use telepharmacy (aged between 55 and 64 years: OR 0.57, 95% CI 0.38-0.86; aged 65 years or older: OR 0.24, 95% CI 0.15-0.37) than those younger than 55 years. Those who rated pharmacy service quality higher were more willing to use telepharmacy (OR 1.06, 95% CI 1.03-1.09) than those who did not. ConclusionsRespondents were generally willing to use telehealth (telemedicine and telepharmacy) services, but the likelihood of their being willing to use telehealth decreased as they were older. For those initially unwilling (aged 55 years or older) to use telemedicine services, inexpensive or insurance-covered services were acceptable.

To mitigate the loss of lives during the COVID-19 pandemic, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with variants susceptible to mAb therapy. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3-4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response antiviral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection.

Background Observational epidemiological studies have reported an association between childhood adiposity and altered cardiac morphology and function in later life. However, whether this is due to a direct consequence of being overweight during childhood has been difficult to establish, particularly as accounting for other measures of body composition throughout the lifecourse can be exceptionally challenging. Methods and Results In this study, we used human genetics to investigate this using a causal inference technique known as lifecourse Mendelian randomization. This approach allowed us to evaluate the effect of childhood body size on 11 measures of right heart and pulmonary circulation independent of other anthropometric traits at various stages in the lifecourse. We found strong evidence that childhood body size has a direct effect on an enlarged right heart structure in later life (eg, right ventricular end‐diastolic volume: β=0.24 [95% CI, 0.15–0.33]; P=3×10−7) independent of adulthood body size. In contrast, childhood body size effects on maximum ascending aorta diameter attenuated upon accounting for body size in adulthood, suggesting that this effect is likely attributed to individuals remaining overweight into later life. Effects of childhood body size on pulmonary artery traits and measures of right atrial function became weaker upon accounting for adulthood fat‐free mass and childhood height, respectively. Conclusions Our findings suggest that, although childhood body size has a long‐term influence on an enlarged heart structure in adulthood, associations with the other structural components of the cardiovascular system and their function may be largely attributed to body composition at other stages in the lifecourse.

Abstract Heart rate variability (HRV) is a cardiac autonomic marker with predictive value in cardiac patients. Ultra-short HRV (usHRV) can be measured at scale using standard and wearable ECGs, but its association with cardiovascular events in the general population is undetermined. We aimed to validate usHRV measured using ≤ 15-s ECGs (using RMSSD, SDSD and PHF indices) and investigate its association with atrial fibrillation, major adverse cardiac events, stroke and mortality in individuals without cardiovascular disease. In the National Survey for Health and Development (n = 1337 participants), agreement between 15-s and 6-min HRV, assessed with correlation analysis and Bland–Altman plots, was very good for RMSSD and SDSD and good for PHF. In the UK Biobank (n = 51,628 participants, 64% male, median age 58), after a median follow-up of 11.5 (11.4–11.7) years, incidence of outcomes ranged between 1.7% and 4.3%. Non-linear Cox regression analysis showed that reduced usHRV from 15-, 10- and 5-s ECGs was associated with all outcomes. Individuals with low usHRV (

Background: This study examines the implementation and perceptions of a pharmacist consultant deprescribing program aimed at reducing the risk of falls in older adults using opioids and benzodiazepines. Methods: This qualitative study conducted interviews with healthcare providers. The interviews were conducted from August to December 2021 and analyzed using inductive coding techniques. Results: Five participants, predominantly female MDs or PA-Cs from rural clinics, were interviewed. The participants adopted a pharmacist-led deprescribing program due to their heightened awareness of the opioid crisis, dedication to patient safety, and a desire for opioid deprescribing education. Initially, concerns included patient resistance and provider-driven barriers. However, over time, patient attitudes shifted toward greater openness to the program. The providers emphasized several critical needs for the success of the program: guaranteed access to pharmacists, tailored patient education, resources specific to providers, and financial support, including telehealth options. These factors were deemed essential to overcoming initial barriers and ensuring effective implementation. Conclusion: Integrating pharmacists into primary care settings shows promise for deprescribing opioids and benzodiazepines in older adults. Future research should explore telehealth options for patient–pharmacist consultations and expand the application of these findings to other healthcare settings. The study highlights the importance of awareness, patient education, access to resources (pharmacists), and provider support in addressing deprescribing among older adults.

Understanding an animal’s diet is a crucial component of conservation, but diet data are often labor intensive to collect and are frequently scarce. Atlantic Puffins ( Fratercula arctica ; hereafter Puffins) are vulnerable to global extinction and have declined in some parts of their UK and Irish range. Differences in population trajectories may relate to diet, but Puffin diet data are currently only collected at a handful of colonies. We explored whether citizen science could address this data gap by inviting visitors to Puffin colonies in 2017 to submit their photographs of Puffins carrying prey. In total, 602 people submitted 1402 images from 35 colonies. We identified the species group, size, and number of prey items in each bill load. Photograph quality was excellent, with 89% of birds in images providing useable diet information. In total 11,150 prey items were counted and measured from 1198 Puffins across 27 colonies. We demonstrated a lack of bias in the sample of photos provided by citizen scientists and described how Puffin chick diet varies in prey composition, prey length, number of prey per bill load, and load biomass over large spatial scales and throughout the breeding season. The diet of Puffin chicks from regions where severe declines have occurred, most notably Shetland, were characterized by a lower prey biomass, higher numbers of fish per load, and a high proportion of small, transparent sandeels consistently through the season. By contrast, in regions where Puffin populations are thought to be increasing, load biomass was high, the number of prey per load low, and larger non-transparent sandeels were the dominant prey, which persisted right through the breeding season. Results from our study show colonies and regions where birds may be expending more effort (collecting more prey items) for lesser returns (lower load biomass) and emphasize the value of collecting diet data across large spatial scales.

Abstract The pathogenesis of exercise intolerance and persistent fatigue which can follow an infection with the SARS‐CoV‐2 virus (“long COVID”) is not fully understood. Cases were recruited from a long COVID clinic (N = 32; 44 ± 12 years; 10 (31%) men), and age‐/sex‐matched healthy controls (HC) (N = 19; 40 ± 13 years; 6 (32%) men) from University College London staff and students. We assessed exercise performance, lung and cardiac function, vascular health, skeletal muscle oxidative capacity, and autonomic nervous system (ANS) function. Key outcome measures for each physiological system were compared between groups using potential outcome means (95% confidence intervals) adjusted for potential confounders. Long COVID participant outcomes were compared to normative values. When compared to HC, cases exhibited reduced oxygen uptake efficiency slope (1847 (1679, 2016) vs. 2176 (1978, 2373) mL/min, p = 0.002) and anaerobic threshold (13.2 (12.2, 14.3) vs. 15.6 (14.4, 17.2) mL/kg/min, p

Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) was initiated by the US government to rapidly develop and test vaccines and therapeutics against COVID-19 in 2020. The ACTIV Therapeutics-Clinical Working Group selected ACTIV trial teams and clinical networks to expeditiously develop and launch master protocols based on therapeutic targets and patient populations. The suite of clinical trials was designed to collectively inform therapeutic care for COVID-19 outpatient, inpatient, and intensive care populations globally. In this report, we highlight challenges, strategies, and solutions around clinical protocol development and regulatory approval to document our experience and propose plans for future similar healthcare emergencies.

ObjectivesWe examined services to facilitate access to entering substance use disorder (SUD) treatment among a national sample of SUD treatment facilities.MethodsWe analyzed data from the National Survey of Substance Abuse Treatment Services (N-SSATS) 2020. Facilities were included in the sample based on criteria such as SUD treatment provision and being in the U.S. Cluster analysis was conducted using variables including ownership, levels of care, and whether facilities provide services or accept payment options aimed at reducing treatment barriers. National and state-level data on the percentage of facilities in each cluster were presented.ResultsAmong N = 15,788 SUD treatment facilities four distinct clusters were identified: Cluster 1 consisted of for-profit and government outpatient facilities with high proportions of services to reduce barriers (22.2%). Cluster 2, comprised of non-profit outpatient facilities, offered the most comprehensive array of services to minimize barriers to treatment among all four clusters (25.2%). Cluster 3 included facilities with diverse ownership and care levels and provided a moderate to high degree of services aimed at reducing entry barriers to treatment (26.0%). Cluster 4 was primarily for-profit outpatient facilities with a low proportion of these services (26.6%).ConclusionsThis study revealed facility-level groupings with different services to reduce barriers to SUD treatment across various clusters of SUD treatment facilities. While some facilities offered extensive services, others provided fewer. Differences in cluster distributions point to possible facilitators to treatment access for some persons seeking admission to specific treatment facilities. Efforts should be made to ensure that individuals seeking SUD treatment can access these services, and facilities should be adequately equipped to meet their diverse needs.

The quantification of aerosol size distributions is crucial for understanding the climate and health impacts of aerosols, validating models, and identifying aerosol sources. This work provides one of the first continuous measurements of aerosol size distribution from 1.02 to 8671 nm near the shore of Lake Michigan. The data were collected during the Lake Michigan Ozone Study (LMOS 2017), a comprehensive air quality measurement campaign in May and June 2017. The time-resolved (2-min) size distribution are reported herein alongside meteorology, remotely sensed data, gravimetric filters, and gas-phase variables. Mean concentrations of key aerosol parameters include PM2.5 (6.4 μg m-3), number from 1 to 3 nm (1.80x104 cm-3) and number greater than 3 nm (8x103 cm-3). During the field campaign, approximately half of days showed daytime ultrafine burst events, characterized by particle growth from sub 10 nm to 25-100 nm. A specific investigation of ultrafine lake spray aerosol was conducted due to enhanced ultrafine particles in onshore flows coupled with sustained wave breaking conditions during the campaign. Upon closer examination, the relationships between the size distribution, wind direction, wind speed, and wave height did not qualitatively support ultrafine particle production from lake spray aerosol; statistical analysis of particle number and wind speed also failed to show a relationship. The alternative hypothesis of enhanced ultrafine particles in onshore flow originating mainly from new particle formation activity is supported by multiple lines of evidence.

Background: The opioid crisis in the US is a severe public health issue, prompting pharmacists to adopt various strategies for prevention, harm reduction, treatment, and recovery. Despite progress, barriers persist. Results: This commentary examines five determinants of public health in relation to pharmacist-led interventions for the opioid crisis: individual behavior, social factors, policymaking, health service accessibility, and biological/genetic considerations. Pharmacists can influence individual behavior through education and support, address social determinants like stigma, advocate for policy changes, ensure health service accessibility, and personalize opioid prescriptions based on biological factors. Conclusion: Pharmacists play a crucial role in addressing the opioid crisis by navigating these determinants. Pharmacists’ engagement is essential for reducing opioid-related harms and improving public health outcomes through advocacy, service provision, and education.

Opioids remain commonly prescribed in older adults, despite the known association with falls and fall-related injuries. This retrospective cohort study sought to determine the association of opioid use and falls in older adult opioid users. Using a one-year lookback period in electronic health records, daily morphine milligram equivalents (MMEs) were calculated using prescription orders. Fall history was based on patient self-reporting. A receiver operating characteristic (ROC) curve was used to identify the threshold of average daily MMEs at which the likelihood of falls was increased. Older opioid users were most often women and White, with 30% having fallen in the prior year. In ROC analyses (n = 590), the threshold where fall risk increased was 37 MMEs (p = 0.07). Older adults prescribed more than 37 MMEs daily may be at increased fall risk and should be targeted for deprescribing interventions. Additionally, analysis on patient characteristics and covariates suggest that sex, age, COPD, sleep apnea, cancer, and psychiatric conditions may indicate an increased risk of falls in older adults taking chronic opioids (p < 0.05). Multifactorial interventions may be needed to modify fall risk beyond medication use alone.

Recent satellite measurements of glacier mass balances show mountain glaciers all over the world had generally negative mass balances in the first decades of the 21st century. Mean summer temperatures all over the world rose from the 1961–1990 period to the 1991–2020 period, implying increasingly negative mass balances. We studied archived annual balances for 38 northern hemisphere glaciers to assess changes within the 1961–2020 period. We used a modified double-mass curve to visualize mass balance changes occurring around 1990. Mean balances in 1961–1990 were already small negative for many of the studied glaciers and became even more negative in 1991–2020 for glaciers in the Alps, at high latitudes and in western North America. The largest mass balance changes were for some glaciers in the Alps. We are unable to explain the lack of change in mean balance for one glacier in High Mountain Asia. We found complex changes for eight glaciers in Scandinavia, even including one glacier with a positive balance. We explain these changes by visualizing the deviations in winter and summer balances from their respective 1961–1990 mean values. High winter balances in the 1990s for Scandinavia partly obscured the emerging trend of increasingly negative summer balances, which we expect to continue in the future.

Objective Undifferentiated, early inflammatory arthritis (EIA) can differentiate into seropositive or seronegative rheumatoid arthritis (RA), peripheral spondyloarthritis (SpA) or remain as seronegative undifferentiated inflammatory arthritis (UIA). Little is known about immune pathways active in the early stages of SpA and seronegative UIA, in contrast to detailed knowledge of seropositive RA. The aim of this study was to examine if specific immune pathways were active in synovial CD4+ and CD8+ T cells in EIA.Methods Synovial fluid (SF) samples from 30 patients with EIA were analysed for expression of IL-17A, IFNγ and TNFα in CD8+ or CD4+ T cells. Final clinical diagnoses were made at least 12 months after sample collection, by two independent clinicians blind to the study data.Results Flow cytometry analysis of all EIA samples indicated considerable variation in synovial IL-17A+CD8+ T cells (Tc17) cell frequencies between patients. The group with a final diagnosis of SpA (psoriatic arthritis or peripheral SpA, n=14) showed a significant enrichment in the percentage of synovial Tc17 cells compared with the group later diagnosed with seronegative UIA (n=10). The small number of patients later diagnosed with seropositive RA (n=6) patients had few Tc17 cells, similar to our previous findings in established disease. In contrast, RA SF contained a significantly higher percentage of CD8+IFNγ+ T cells compared with SpA or seronegative UIA.Conclusion These results suggest that adaptive T cell cytokine pathways differ not only between RA and SpA but also seronegative UIA early in the disease process, with a particular activation of Tc17 pathways in early SpA.