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Soil moisture predictions from land surface models are important in hydrological, ecological, and meteorological applications. In recent years, the availability of wide-area soil moisture measurements has increased, but few studies have combined model-based soil moisture predictions with in situ observations beyond the point scale. Here we show that we can markedly improve soil moisture estimates from the Joint UK Land Environment Simulator (JULES) land surface model using field-scale observations and data assimilation techniques. Rather than directly updating soil moisture estimates towards observed values, we optimize constants in the underlying pedotransfer functions, which relate soil texture to JULES soil physics parameters. In this way, we generate a single set of newly calibrated pedotransfer functions based on observations from a number of UK sites with different soil textures. We demonstrate that calibrating a pedotransfer function in this way improves the soil moisture predictions of a land surface model at 16 UK sites, leading to the potential for better flood, drought, and climate projections.

The COSMOS-UK observation network has been providing field-scale soil moisture and hydrometeorological measurements across the UK since 2013. At the time of publication a total of 51 COSMOS-UK sites have been established, each delivering high-temporal resolution data in near-real time. Each site utilizes a cosmic-ray neutron sensor, which counts epithermal neutrons at the land surface. These measurements are used to derive field-scale near-surface soil water content, which can provide unique insight for science, industry, and agriculture by filling a scale gap between localized point soil moisture and large-scale satellite soil moisture datasets. Additional soil physics and meteorological measurements are made by the COSMOS-UK network including precipitation, air temperature, relative humidity, barometric pressure, soil heat flux, wind speed and direction, and components of incoming and outgoing radiation. These near-real-time observational data can be used to improve the performance of hydrological models, validate remote sensing products, improve hydro-meteorological forecasting, and underpin applications across a range of other scientific fields. The most recent version of the COSMOS-UK dataset is publically available at https://doi.org/10.5285/b5c190e4-e35d-40ea-8fbe-598da03a1185 (Stanley et al., 2021).

Pedotransfer functions are used to relate gridded databases of soil texture information to the soil hydraulic and thermal parameters of land surface models. The parameters within these pedotransfer functions are uncertain and calibrated through analyses of point soil samples. How these calibrations relate to the soil parameters at the spatial scale of modern land surface models is unclear because gridded databases of soil texture represent an area average. We present a novel approach for calibrating such pedotransfer functions to improve land surface model soil moisture prediction by using observations from the Soil Moisture Active Passive (SMAP) satellite mission within a data assimilation framework. Unlike traditional calibration procedures, data assimilation always takes into account the relative uncertainties given to both model and observed estimates to find a maximum likelihood estimate. After performing the calibration procedure, we find improved estimates of soil moisture and heat flux for the Joint UK Land Environment Simulator (JULES) land surface model (run at a 1 km resolution) when compared to estimates from a cosmic-ray soil moisture monitoring network (COSMOS-UK) and three flux tower sites. The spatial resolution of the COSMOS probes is much more representative of the 1 km model grid than traditional point-based soil moisture sensors. For 11 cosmic-ray neutron soil moisture probes located across the modelled domain, we find an average 22 % reduction in root mean squared error, a 16 % reduction in unbiased root mean squared error and a 16 % increase in correlation after using data assimilation techniques to retrieve new pedotransfer function parameters.

Abstract Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7 Cre-ER-T2/+ ; Nras LSL-G12D/+ ; p53 fl/fl (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse 13C-labeled glucose or glutamine into mice with sarcomas and show that sarcomas consume more glucose and glutamine than healthy muscle tissue. However, we reveal a marked shift from glucose consumption to glutamine metabolism after radiation therapy (RT). In addition, we show that inhibiting glutamine, either through genetic deletion of glutaminase (Gls1) or through pharmacological inhibition of glutaminase, leads to significant radiosensitization in vivo. This causes a significant increase in overall survival for mice with Gls1-deficient compared to Gls1-proficient sarcomas. Finally, Gls1-deficient sarcomas post-RT elevate levels of proteins involved in natural killer cell and interferon alpha/gamma responses, suggesting a possible role of innate immunity in the radiosensitization of Gls1-deficient sarcomas. Thus, our results indicate that glutamine contributes to radiation response in a mouse model of RMS.

Abstract Environmental DNA (eDNA) degradation influences the effectiveness of eDNA‐based biodiversity monitoring, but the factors that determine the rate of decay of eDNA in terrestrial environments are poorly understood. We assessed the persistence of vertebrate eDNA from a mock vertebrate community created with soil from zoo enclosures holding 10 target species from different taxonomic classes (reptiles, birds, and mammals) and of different biomass (little penguin and giraffe). We examined species detection rates resulting from eDNA metabarcoding, as well as relative eDNA concentrations via qPCR, from soil samples over eight time points (0–12 weeks), during exposure to three ambient temperatures (10, 25, and 40°C) and three levels of ultraviolet B (UV‐B) radiation (0%, 50%, and 100% intensity). We recorded considerable variation in detectability between species, independent of temperature, and UV‐B effects. Quantitative polymerase chain reaction (PCR) indicated degradation of eDNA over time for all temperature and UV treatments, although it was still possible to detect eDNA from some species after 12 weeks. Degradation rates were lowest for high UV‐B treatments, presumably due to UV‐B reducing bacterial metabolism. The temperatures investigated did not influence eDNA decay. Our results indicate that eDNA in soil can persist under a range of temperatures and high UV radiation for longer than expected. Sheltered sites with minimal UV‐B radiation, which have previously been considered ideal sites for terrestrial eDNA collection, may not be optimal for eDNA persistence in some cases due to microbial decay. A better understanding of eDNA degradation in terrestrial environments is needed to enhance the accuracy of eDNA metabarcoding for surveying terrestrial vertebrate communities.

Abstract Background Intimate partner violence (IPV) remains a pervasive and complex issue with significant social and public health implications. The nexus of firearms and intimate partner violence (IPV) is an especially dangerous one. However, little is known about how firearm involvement can influence the risk of repeat IPV assaults. Methods We use data from 346 male perpetrated IPV incidents reported to the Detroit Police Department between December 2016 and April 2017 to examine the role of firearm involvement in IPV recidivism during a 5 and half year follow up period. Employing a conditional gap-time frailty model that accommodates heterogeneity among individuals through a frailty term, we analyze time to multiple IPV assaults that occur over the follow up period. We identify various pathways through which firearms impact the likelihood of subsequent IPV incidents, including intimidation, threats, and use of firearms, while controlling for observable perpetrator characteristics to understand the explicit roles of firearms. Results Firearm involvement at the index assault was not associated with IPV recidivism. However, involvement of firearms in past IPV assaults significantly increased the risk of subsequent physical IPV. The discrepancy is likely arising from a high degree of censoring among individuals who were armed with a firearm during the index assault. Conclusion Our research reveals a nuanced relationship between firearm involvement and IPV recidivism, shedding light on the multifaceted dynamics at play. By elucidating the intricate dynamics at the intersection of firearms and intimate partner violence, our study underscores the need for targeted policy interventions and preventative measures aimed at reducing IPV recidivism.

Abstract Background Peer support for mental health is recommended across international policy guidance and provision. Our systematic umbrella review summarises evidence on the effectiveness, implementation, and experiences of paid peer support approaches for mental health. Methods We searched MEDLINE, EMBASE, PsycINFO, The Campbell Collaboration, and The Cochrane Database of Systematic Reviews (2012–2022) for reviews of paid peer support interventions for mental health. The AMSTAR2 assessed quality. Results were synthesised narratively, with implementation reported using the CFIR (Consolidated Framework for Implementation Research). The protocol was registered with PROSPERO (registration number: CRD42022362099). Results We included 35 reviews (426 primary studies, n = 95–40,927 participants): systematic reviews with (n = 13) or without (n = 13) meta-analysis, or with qualitative synthesis (n = 3), scoping reviews (n = 6). Most reviews were low or critically low (97%) quality, one review was high quality. Effectiveness was investigated in 23 reviews. Results were mixed; there was some evidence from meta-analyses that peer support may improve depression symptoms (particularly perinatal depression), self-efficacy, and recovery. Factors promoting successful implementation, investigated in 9 reviews, included adequate training and supervision, a recovery-oriented workplace, strong leadership, and a supportive and trusting workplace culture with effective collaboration. Barriers included lack of time, resources and funding, and lack of recognised peer support worker (PSW) certification. Experiences of peer support were explored in 11 reviews, with 3 overarching themes: (i) what the PSW role can bring, including recovery and improved wellbeing for service users and PSWs; (ii) confusion over the PSW role, including role ambiguity and unclear boundaries; and (iii) organisational challenges and impact, including low pay, negative non-peer staff attitudes, and lack of support and training. Conclusions Peer support may be effective at improving some clinical outcomes, self-efficacy, and recovery. Certain populations, e.g. perinatal populations, may especially benefit from peer support. Potential strategies to successfully implement PSWs include co-production, clearly defined PSW roles, a receptive hierarchical structure and staff, appropriate PSW and staff training with clinical and/or peer supervision alongside safeguarding. Services could benefit from clear, coproduced, setting specific implementation guidelines for PSW. PSW roles tend to be poorly defined and associations between PSW intervention content and impacts need further investigation. Future research should reflect the priorities of providers/service users involved in peer support.

Abstract CRISPR screens with single-cell transcriptomic readouts are a valuable tool to understand the effect of genetic perturbations including single nucleotide variants (SNVs) associated with diseases. Interpretation of these data is currently limited as genotypes cannot be accurately inferred from guide RNA identity alone. scSNV-seq overcomes this limitation by coupling single-cell genotyping and transcriptomics of the same cells enabling accurate and high-throughput screening of SNVs. Analysis of variants across the JAK1 gene with scSNV-seq demonstrates the importance of determining the precise genetic perturbation and accurately classifies clinically observed missense variants into three functional categories: benign, loss of function, and separation of function.

Alterations in the gut-microbiome-brain axis are increasingly being recognized to be involved in Alzheimer’s disease (AD) pathogenesis. However, the functional consequences of enteric dysbiosis linking gut microbiota and brain pathology in AD progression remain largely undetermined. The present work investigated the causal role of age-associated temporal decline in butyrate-producing bacteria and butyrate in the etiopathogenesis of AD. Longitudinal metagenomics, neuropathological, and memory analyses were performed in the 3×Tg-AD mouse model. Metataxonomic analyses showed a significant temporal decline in the alpha diversity marked by a decrease in butyrate-producing bacterial communities and a concurrent reduction in cecal butyrate production. Inferred metagenomics analysis identified the bacterial acetyl-CoA pathway as the main butyrate synthesis pathway impacted. Concomitantly, there was an age-associated decline in the transcriptionally permissive acetylation of histone 3 at lysines 9 and 14 (H3K9/K14-Ac) in hippocampal neurons. Importantly, these microbiome-gut-brain changes preceded AD-related neuropathology, including oxidative stress, tau hyperphosphorylation, memory deficits, and neuromuscular dysfunction, which manifest by 17–18 months. Initiation of oral administration of tributyrin, a butyrate prodrug, at 6 months of age mitigated the age-related decline in butyrate-producing bacteria, protected the H3K9/K14-Ac status, and attenuated the development of neuropathological and cognitive changes associated with AD pathogenesis. These data causally implicate age-associated decline in butyrate-producing bacteria as a key pathogenic feature of the microbiome-gut-brain axis affecting the onset and progression of AD. Importantly, the regulation of butyrate-producing bacteria and consequent butyrate synthesis could be a significant therapeutic strategy in the prevention and treatment of AD.

Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network–targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: β = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: β = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Abstract Objective Roller swabbing of surfaces is an effective way to obtain environmental DNA, but the current DNA extraction method for these samples is equipment heavy, time consuming, and increases potential contamination through multiple handling. Here, we used rollers to swab a dog kennel and compared three DNA extraction approaches (water filtration, roller trimming and direct buffer) using two different platforms (Qiacube, Kingfisher). DNA extraction methods were evaluated based on cost, effort, DNA concentration and PCR result. Results The roller trim method emerged as the optimal method with the best PCR results, DNA concentration and cost efficiency, while the buffer-based methods were the least labour intensive but produced mediocre PCR results and DNA concentrations. Additionally, the Kingfisher magnetic bead extractions generally ranked higher in all categories over the Qiacube column-based DNA extractions. Ultimately, the ideal DNA extraction method for a particular study is influenced by logistical constraints in the field such as the size of the roller, the availability of cold storage, and time constraints on the project. Our results demonstrate the strengths and weaknesses of each approach, allowing for informed decision making by researchers.

Background: Colorectal cancer is the fourth most common cancer in the US. Many of these patients will require operations. Although there is significant data in the literature that supports minimally invasive colorectal operations in the academic setting, few studies have examined their performance in community hospitals. Methods: Data was collected from a high-volume, university-affiliated, community center. Our Cancer Registry Database was queried to include any patients that had rectal surgery at our institution from 2010 to 2020. One hundred-twenty-two patients were identified and reviewed retrospectively. Main outcome measures include estimated blood loss (EBL), blood transfusion, time to first bowel movement, oncologic resection, length of stay (LOS), survival, and cost analysis. Results: Both robotic and laparoscopic operations resulted in lower average EBL, less blood transfusions, and less time to first bowel movement (p = 0.003, 0.006, 0.003, respectively). There was no significant difference in ability to achieve R0 resection, adequate lymph node retrieval, and adequate total mesorectal excision (TME, p = 0.856, 0.489, 0.500, respectively). LOS was significantly shorter for minimally invasive operations, 4.35 vs 8.48 days, and average survival was longest for laparoscopic operations at 7.19 years as compared to 5.55 years for open operations (p

Rationale & Objective: Kidney function progressively declines in most patients with type 2 diabetes (T2DM). Many develop progressive chronic kidney disease (CKD), but some experience a more rapid decline, with a greater risk of kidney failure and cardiovascular disease. In EMPA-REG OUTCOME, empagliflozin was associated with slower kidney disease progression. This post hoc analysis evaluated the effect of empagliflozin (pooled doses) on the prevalence of a “rapid decliner” phenotype, defined by an annual estimated glomerular filtration rate (eGFR) decline of >3 mL/min/1.73 m2. Study Design: This was an exploratory analysis of EMPA-REG OUTCOME, a large randomized, double-blind, placebo-controlled trial in adults with T2DM, established cardiovascular disease and an eGFR of ≥30 mL/min/1.73 m2. Setting & Participants: Analysis was undertaken on 6,967 participants (99.2%) in whom serial eGFR data was available. Interventions: Patients were randomized (1:1:1) to empagliflozin 10 mg, 25 mg, or placebo in addition to standard of care. Outcomes: Annual change in eGFR over the maintenance phase of treatment (week 4 to last value on treatment) was calculated using linear regression models. Logistic regression analysis was used to investigate differences in rapid decline between the treatment groups. Results: Over the study period, a rapid decliner phenotype was observed in 188 (9.5%) participants receiving placebo and 134 (3.4%) receiving empagliflozin. After adjusting for other risk factors, this equated to a two-third reduction in odds (OR, 0.32; 95% CI, 0.25-0.40; P 5 mL/min/1.73 m2/y (empagliflozin vs placebo, 43 [1.1%] vs 44 [2.2%] participants; OR, 0.47; 95% CI, 0.31-0.72; P

The thalamus is a centrally located and heterogeneous brain structure that plays a critical role in various sensory, motor, and cognitive processes. However, visualizing the individual subnuclei of the thalamus using conventional MRI techniques is challenging. This difficulty has posed obstacles in targeting specific subnuclei for clinical interventions such as deep brain stimulation (DBS). In this paper, we present DiMANI, a novel method for directly visualizing the thalamic subnuclei using diffusion MRI (dMRI). The DiMANI contrast is computed by averaging, voxelwise, diffusion-weighted volumes enabling the direct distinction of thalamic subnuclei in individuals. We evaluated the reproducibility of DiMANI through multiple approaches. First, we utilized a unique dataset comprising 8 scans of a single participant collected over a 3-year period. Secondly, we quantitatively assessed manual segmentations of thalamic subnuclei for both intra-rater and inter-rater reliability. Thirdly, we qualitatively correlated DiMANI imaging data from several patients with Essential Tremor with the localization of implanted DBS electrodes and clinical observations. Lastly, we demonstrated that DiMANI can provide similar features at 3T and 7T MRI, using varying numbers of diffusion directions. Our results establish that DiMANI is a reproducible and clinically relevant method to directly visualize thalamic subnuclei. This has significant implications for the development of new DBS targets and the optimization of DBS therapy.

Sodium‐glucose co-transporter 2 (SGLT2) inhibitors have recently emerg ed as an effective means to protect kidney function in people with type 2 diabetes and chronic kidney disease (CKD). In this review, we explore the role of SGLT2 inhibition in these individuals. SGLT2 inhibitors specifically act to inhibit sodium and glucose reabsorption in the early proximal tubule of the renal nephron. Although originally developed as glucose-lowering agents through their ability to induce glycosuria, it became apparent in cardiovascular outcome trials that the trajectory of kidney function decline w as significantly slowed and the incidence of serious falls in kidney function was reduced in participants receiving an SGLT2 inhibitor. These observations have recently led to spe cific outcome trials in participants with CKD, including DAPA-CKD, CREDENCE and EMPA-KIDNEY, and real-world studies, like CVD-REAL-3, that have confirmed the observation of kidney benefits in this setting. In response, recent KDIGO Guidelines have recommended the use of SGLT2 inhibitors as first-line therapy in patients with CKD, alongside statins, renin–angiotensin– aldosterone system inhibitors and multifactorial risk factor management as indicated. However, SGLT2 inhibitors remain significantly underutilized in the setting of CKD. Indeed, an inertia paradox exists, with patients with more severe disease less likely to receive an SGLT2 inhibitor. Concerns regarding safety appear unfounded, as acute kidney injury, hyperkalaemia, major acute cardiovascular events and cardiac death in patients with CKD appear to be lower following SGLT2 inhibition. The first-in-clas s indication of dapagliflozin for CKD may begin a new approach to managing kidney disease in type 2 diabetes.

ObjectiveTo characterize how the proximity of deep brain stimulation (DBS) active contact locations relative to the cerebellothalamic tract (CTT) affect clinical outcomes in patients with essential tremor (ET).BackgroundDBS is an effective treatment for refractory ET. However, the role of the CTT in mediating the effect of DBS for ET is not well characterized. 7-Tesla (T) MRI-derived tractography provides a means to measure the distance between the active contact and the CTT more precisely.MethodsA retrospective review was conducted of 12 brain hemispheres in 7 patients at a single center who underwent 7T MRI prior to ventral intermediate nucleus (VIM) DBS lead placement for ET following failed medical management. 7T-derived diffusion tractography imaging was used to identify the CTT and was merged with the post-operative CT to calculate the Euclidean distance from the active contact to the CTT. We collected optimized stimulation parameters at initial programing, 1- and 2-year follow up, as well as a baseline and postoperative Fahn-Tolosa-Marin (FTM) scores.ResultsThe therapeutic DBS current mean (SD) across implants was 1.8 mA (1.8) at initial programming, 2.5 mA (0.6) at 1 year, and 2.9 mA (1.1) at 2-year follow up. Proximity of the clinically-optimized active contact to the CTT was 3.1 mm (1.2), which correlated with lower current requirements at the time of initial programming (R2 = 0.458, p = 0.009), but not at the 1- and 2-year follow up visits. Subjects achieved mean (SD) improvement in tremor control of 77.9% (14.5) at mean follow-up time of 22.2 (18.9) months. Active contact distance to the CTT did not predict post-operative tremor control at the time of the longer term clinical follow up (R2 = -0.073, p = 0.58).ConclusionActive DBS contact proximity to the CTT was associated with lower therapeutic current requirement following DBS surgery for ET, but therapeutic current was increased over time. Distance to CTT did not predict the need for increased current over time, or longer term post-operative tremor control in this cohort. Further study is needed to characterize the role of the CTT in long-term DBS outcomes.

Abstract The use of anthropogenic resources is becoming increasingly common as species adapt to human‐induced environmental changes, but their use can expose species to new risks. Understanding how animals exploit these resources is important for guiding conservation management, particularly where species are threatened. The introduction of canola cropping to breeding areas of endangered Carnaby's cockatoo (Zanda latirostris) has been attributed to an increase in the birds' reproductive success; however, the seed may be protein‐limiting for nestling growth and its use by cockatoos has been implicated in the emergence of a new disease. We used high‐resolution accelerometer‐capable GPS tags to track eight birds. Accelerometer data were used to calculate overall dynamic body acceleration (ODBA), a proxy for energy expenditure, and to identify and quantify canola and native vegetation foraging behaviours. We used linear mixed models to determine which factors affected patterns of resource use and to determine whether, and to what extent, canola use was associated with reduced energetic and movement costs. We then compared the energetic content of canola seed and native food sources to inform patterns of behaviour and habitat use revealed by our tracking data. Use of canola was associated with reduced movement costs and energy expenditure. However, there was an apparent reluctance to increase foraging on canola above a threshold of time, even when conditions reduced time available to utilise native food sources. While anthropogenic resources may appear to improve population trends in some cases, careful investigations of patterns of resource use are necessary to guide appropriate conservation management efforts. For Carnaby's cockatoos, conservation efforts should focus on retention, protection and expansion of native food sources.

Background: While deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear. Methods: Using ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects. Results: The lateral portion of the CTT had the highest activation at clinical settings (p

Chronic hyperglycemia induces intrarenal oxidative stress due to the excessive production of reactive oxygen species (ROS), leading to a cascade of events that contribute to the development and progression of diabetic kidney disease (DKD). NOX5, a pro-oxidant NADPH oxidase isoform, has been identified as a significant contributor to renal ROS in humans. Elevated levels of renal ROS contribute to endothelial cell dysfunction and associated inflammation, causing increased endothelial permeability, which can disrupt the renal ecosystem, leading to progressive albuminuria and renal fibrosis in DKD. This study specifically examines the contribution of endothelial cell-specific human NOX5 expression in renal pathology in a transgenic mouse model of DKD. This study additionally compares NOX5 with the previously characterized NADPH oxidase, NOX4, in terms of their relative roles in DKD. Regardless of NOX4 pathway, this study found that endothelial cell-specific expression of NOX5 exacerbates renal injury, albuminuria and fibrosis. This is attributed to the activation of the endothelial mesenchymal transition (EMT) pathway via enhanced ROS formation and the modulation of redox-sensitive factors. These findings underscore the potential therapeutic significance of NOX5 inhibition in human DKD. The study proposes that inhibiting NOX5 could be a promising approach for mitigating the progression of DKD and strengthens the case for the development of NOX5-specific inhibitors as a potential therapeutic intervention.

IntroductionEvidence suggests that spontaneous beta band (11–35 Hz) oscillations in the basal ganglia thalamocortical (BGTC) circuit are linked to Parkinson’s disease (PD) pathophysiology. Previous studies on neural responses in the motor cortex evoked by electrical stimulation in the subthalamic nucleus have suggested that circuit resonance may underlie the generation of spontaneous and stimulation-evoked beta oscillations in PD. Whether these stimulation-evoked, resonant oscillations are present across PD patients in the internal segment of the globus pallidus (GPi), a primary output nucleus in the BGTC circuit, is yet to be determined.MethodsWe characterized spontaneous and stimulation-evoked local field potentials (LFPs) in the GPi of four PD patients (five hemispheres) using deep brain stimulation (DBS) leads externalized after DBS implantation surgery.ResultsOur analyses show that low-frequency (2–4 Hz) stimulation in the GPi evoked long-latency (>50 ms) beta-band neural responses in the GPi in 4/5 hemispheres. We demonstrated that neural sources generating both stimulation-evoked and spontaneous beta oscillations were correlated in their frequency content and spatial localization.DiscussionOur results support the hypothesis that the same neuronal population and resonance phenomenon in the BGTC circuit generates both spontaneous and evoked pallidal beta oscillations. These data also support the development of closed-loop control systems that modulate the GPi spontaneous oscillations across PD patients using beta band stimulation-evoked responses.

In both Western and East Asian traditions, large claims have been made about the power of aesthetic experience, whether of art (especially music) or of nature, to foster a sense of transcendence. There are, however, important differences between the traditions and, in consequence, between the characters of these claims. After illustrating these claims, I identify and elaborate on some of their salient aspects. I then argue that East Asian traditions possess greater resources than Western ones for explaining or accommodating these aspects, and hence for substantiating the claims about experience and transcendence.

Abstract To elucidate the role of the basal ganglia during REM sleep movements in Parkinson’s disease (PD) we recorded pallidal neural activity from four PD patients. Unlike desynchronization commonly observed during wakeful movements, beta oscillations (13–35 Hz) synchronized during REM sleep movements; furthermore, high-frequency oscillations (150–350 Hz) synchronized during movement irrespective of sleep-wake states. Our results demonstrate differential engagement of the basal ganglia during REM sleep and awake movements.

Abstract Type 1 diabetes (T1D) is an autoimmune disease that selectively destroys insulin-producing β-cells in the pancreas. An unmet need in diabetes management, current therapy is focussed on transplantation. While the reprogramming of progenitor cells into functional insulin-producing β-cells has also been proposed this remains controversial and poorly understood. The challenge is determining why default transcriptional suppression is refractory to exocrine reactivation. After the death of a 13-year-old girl with established insulin-dependent T1D, pancreatic cells were harvested in an effort to restore and understand exocrine competence. The pancreas showed classic silencing of β-cell progenitor genes with barely detectable insulin (Ins) transcript. GSK126, a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of core β-cell markers and ductal progenitor genes. GSK126 also reinstated Ins gene expression despite absolute β-cell destruction. These studies show the refractory nature of chromatin characterises exocrine suppression influencing β-cell plasticity. Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population.

El conjunto de arte rupestre de Isla de Mona (nombre indígena Amona), en su mayor parte relacionado con la dilatada ocupación indígena, es uno de los más diversos y abundantes de las Antillas. Desde el año 2013, nuestro proyecto se focaliza en la historia indígena de la isla, reelaborando los trabajos anteriores realizados por el Dr. Ovidio Dávila Dávila durante los años 80 y 90 y el Dr. Irving Rouse en los años 30 del siglo xx. En este artículo consideramos algunos aspectos de las prácticas subterráneas que quedaron marginadas porque difieren de lo que normalmente consideramos como arte rupestre. En Mona la morfología de las cuevas y las características de las superficies subterráneas fomentan actividades ocultas que incluyen las interacciones con sustancias minerales y distintas formas de dejar imágenes y marcas, y de transitar el espacio. En particular analizamos la práctica común de trazar huellas digitales en los carbonatos suaves y pastosos de las paredes usando las manos, una técnica que observamos en las áreas oscuras de 30 de las aproximadamente 70 cuevas que hemos visitados de un total de 230 cuevas conocidas en la isla. Estos grabados hechos con los dedos, a la misma vez que dejaron huellas negativas y blanquitas, el arte rupestre, también removieron sustancias en actividades acordes a la minería, y a lo que nos referimos como el arte-minería. El arte es minería y la minería es arte. En vez de enfocarnos en las representaciones, nos centramos en la mayoría de las marcas que no son imágenes. Este trabajo es un aporte a los estudios de diferentes partes del mundo donde la relaciones entre el arte rupestre, las cuevas, el uso de minerales subterráneas, y los estados ampliados de conciencia forman ensamblajes dinámicos, conectando Mona con otros espacios subterráneos antillanos, además de con las áreas continentales del centro y norte de América.

Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome-wide methylation patterns are poorly defined. While methylation is known to alter gene expression, the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low. To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n = 39) that was subsequently replicated in a larger validation cohort (n = 296). Gene body–related regions made up more than 60% of the methylation differences and emphasized the importance of methylation sequencing. We observed differentially methylated genes associated with DN in 3 independent T1D registries originating from Denmark (n = 445), Hong Kong (n = 107), and Thailand (n = 130). Reduced DNA methylation at CTCF and Pol2B sites was tightly connected with DN pathways that include insulin signaling, lipid metabolism, and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubule cells. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding, and the activation of insulin-signaling phosphoproteins in hyperglycemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophages and vascular endothelial cells.

Methylglyoxal (MGO) is a reactive glucose metabolite linked to diabetic cardiovascular disease (CVD). MGO levels surge during intermittent hyperglycemia. We hypothesize that these MGO spikes contribute to atherosclerosis, and that pyridoxamine as a MGO quencher prevents this injury. To study this, we intravenously injected normoglycemic 8-week old male C57Bl6 ApoE-/- mice with normal saline (NS, n = 10) or 25 µg MGO for 10 consecutive weeks (MGOiv, n = 11) with or without 1 g/L pyridoxamine (MGOiv+PD, n = 11) in the drinking water. We measured circulating immune cells by flow cytometry. We quantified aortic arch lesion area in aortic roots after Sudan-black staining. We quantified the expression of inflammatory genes in the aorta by qPCR. Intermittent MGO spikes weekly increased atherosclerotic burden in the arch 1.8-fold (NS: 0.9 ± 0.1 vs 1.6 ± 0.2 %), and this was prevented by pyridoxamine (0.8 ± 0.1 %). MGOiv spikes increased circulating neutrophils and monocytes (2-fold relative to NS) and the expression of ICAM (3-fold), RAGE (5-fold), S100A9 (2-fold) and MCP1 (2-fold). All these changes were attenuated by pyridoxamine. This study suggests that MGO spikes damages the vasculature independently of plasma glucose levels. Pyridoxamine and potentially other approaches to reduce MGO may prevent excess cardiovascular risk in diabetes

BackgroundPublic Health England recently called for the establishment of services to help people to safely stop prescribed drugs associated with dependence and withdrawal, including benzodiazepines, z-drugs, antidepressants, gabapentinoids and opioids. NICE identified a lack of knowledge about the best model for such service delivery. Therefore, we performed a global survey of existing deprescribing services to identify common practices and inform service development.MethodsWe identified existing deprescribing services and interviewed key personnel in these services using an interview co-produced with researchers with lived experience of withdrawal. We summarised the common practices of the services and analysed the interviews using a rapid form of qualitative framework analysis.ResultsThirteen deprescribing services were included (8 UK, 5 from other countries). The common practices in the services were: gradual tapering of medications often over more than a year, and reductions made in a broadly hyperbolic manner (smaller reductions as total dose became lower). Reductions were individualised so that withdrawal symptoms remained tolerable, with the patient leading this decision-making in most services. Support and reassurance were provided throughout the process, sometimes by means of telephone support lines. Psychosocial support for the management of underlying conditions (e.g. CBT, counselling) were provided by the service or through referral. Lived experience was often embedded in services through founders, hiring criteria, peer support and sources of information to guide tapering.ConclusionWe found many common practices across existing deprescribing services around the world. We suggest that these ingredients are included in commissioning guidance of future services and suggest directions for further research to clarify best practice.

We evaluate if the iconic Australian Zebra Finch (Taeniopygia guttata) has a unique physiology or if its metabolic, thermal and hygric physiology are similar to other Australian poephiline finches, by comparing it with three other species, the arid-habitat Painted Finch (Emblema pictum) and the mesic-habitat Double-barred (Taeniopygia bichenovii) and Red-browed (Neochmia temporalis) Finches. All physiological variables responded to ambient temperature as expected. There were no species differences for any of the standard physiological variables, consistent with the hypotheses that birds are pre-adapted to arid habitats, the recent development of Australian deserts has limited opportunity for physiological adaptation, and all four species share similar behavioural and ecological traits. Nevertheless, the ambient temperature where metabolic water production equals evaporative water loss (point of relative water economy) was highest for the Zebra (19.1 °C), lower for Double-barred (16.4 °C) and Painted (15.2 °C) and lowest for Red-Browed (4.1 °C) Finches, corresponding with their general patterns of habitat aridity. The point of relative water economy may be a sensitive index for assessing a species’ tolerance of aridity because it integrates individual physiological variables. We conclude that the Zebra Finch is not a physiological outlier amongst Australian finches, but is at the end of a continuum of aridity tolerance for the four study species.

Contextual design and selection of MRI protocols is critical for making an accurate diagnosis given the wide variety of clinical indications for spine imaging in children. Here, we describe our pediatric spine imaging protocols in detail, tailored to specific clinical questions.

Abstract Introduction Auditory neuropathy spectrum disorder (ANSD) is a term for a collection of test results which indicate disruption of the auditory signal at some point along the neural pathway. This results in a spectrum of functional outcomes, ranging from reasonably normal hearing to profound hearing loss. This study assessed brain structure changes and behavioral correlates in children diagnosed with ANSD. Methods Seventeen children who had previously been diagnosed with ANSD were recruited to the study and underwent a battery of behavioral measures of hearing, language, and communication, along with structural MR imaging. Analysis of cortical thickness of temporal lobe structures was carried out using FreeSurfer. Tract‐based spatial statistics were performed on standard diffusion parameters of fractional anisotropy and diffusivity metrics. The control group comprised imaging data taken from a library of MRI scans from neurologically normal children. Control images were matched as closely as possible to the ANSD group for age and sex. Results Reductions in right temporal lobe cortical thickness were observed in children with ANSD compared to controls. Increases in medial diffusivity in areas including the corpus callosum and in the right occipital white matter were also seen in the group with ANSD compared to controls. Speech perception abilities, both in quiet and in noise, were correlated with cortical thickness measurements for several temporal lobe structures in children with ANSD, and relationships were also seen between diffusion metrics and measures of auditory function. Conclusion This study shows that children with ANSD have structural brain differences compared to healthy controls. It also demonstrates associations between brain structure and behavioral hearing abilities in children diagnosed with ANSD. These results show that there is a potential for structural imaging to be used as a biomarker in this population with the possibility of predicting functional hearing outcome.

Freezing of gait (FOG) is a particularly debilitating symptom of Parkinson’s disease (PD) and is often refractory to treatment. A striking feature of FOG is that external sensory cues can be used to overcome freezing and improve gait. Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) and globus pallidus (GP) show that beta-band power modulates with gait phase. In the STN, beta-band oscillations are modulated by external cues, but it is unknown if this relationship holds in the globus pallidus (GP). Here we report LFP data recorded from the left GP, using a Medtronic PC + S device, in a 68-year-old man with PD and FOG during treadmill walking. A “stepping stone” task was used during which stepping was cued using visual targets of constant color or targets that unpredictably changed color, requiring a step length adjustment. Gait performance was quantified using measures of treadmill ground reaction forces and center of pressure and body kinematics from video monitoring. Beta-band power (12–30 Hz) and number of freezing episodes were measured. Cues which unpredictably changed color improved FOG more than conventional cues and were associated with greater modulation of beta-band power in phase with gait. This preliminary finding suggests that cueing-induced improvement of FOG may relate to beta-band modulation.

Aims: To investigate whether renal pathology is an independent predictor for end-stage renal disease (ESRD) in diabetic kidney diseases (DKD) with nephrotic range proteinuria. Methods: A total of 199 DKD patients with nephrotic range proteinuria underwent renal biopsy and were divided into an ESRD group and a non-ESRD group. A Kaplan–Meier analysis was used to compare renal survival rate, and univariate and multivariate Cox proportional hazard analyses were used to determine the predictors of the ESRD. Results: The mean age of included patients was 51.49 ± 9.12 years and 113 patients (56.8%) progressed to ESRD. The median follow-up period was 16 (12–28) months. The glomerular pathology class III is the most common type (54.3%). In the Kaplan–Meier analysis, compared with patients without ESRD, patients with ESRD had a longer duration of diabetes (≥6 years), lower eGFR (2), lower albumin (p < 0.05). The hemoglobin and e-GFR, but not the histopathological damage, were significantly associated with a higher risk of ESRD in both the univariate and multivariate Cox analyses. Conclusions: In patients with diabetic kidney disease characterized by nephrotic range proteinuria, histopathological damage (glomerular alterations, interstitial fibrosis and tubular atrophy (IFTA), interstitial inflammation, and arteriolar hyalinosis) is not associated with poor renal outcomes, but hemoglobin and e-GFR could predict poor renal outcomes.

Eco-concern, the distress experienced relating to climate change, is associated with mental health, yet no study has examined disordered eating related to eco-concern. This study developed and validated a 10-item scale assessing Eating-Related Eco-Concern (EREC). Participants (n = 224) completed the EREC, Climate Change Worry Scale (CCWS), and Eating Disorder Examination-Questionnaire (EDE-Q). Construct validity, convergent validity, and internal consistency were evaluated. Sex differences in EREC were evaluated using t-tests. Associations among the EREC, CCWS, and EDE-Q were evaluated using linear regression models. Sensitivity analyses were conducted in individuals below EDE-Q global score clinical cut-offs. Factor analysis suggested that all items loaded adequately onto one factor. Pearson’s correlation and Bland–Altman analyses suggested strong correlation and acceptable agreement between the EREC and CCWS (r = 0.57), but weak correlation and low agreement with the EDE-Q global score (r = 0.14). The EREC had acceptable internal consistency (α = 0.88). No sex difference was observed in the EREC in the full sample; females had a significantly higher mean score than males in sensitivity analysis. The EREC was significantly positively associated with the CCWS and EDE-Q global and shape concern scores, but not in sensitivity analysis. The EREC is a brief, validated scale that can be useful to screen for eating-related eco-concern.

Background People who have suffered the loss of a loved one may subsequently report sensory experiences of the deceased (termed ‘after-death communications’, or ADCs). Such encounters are common and can be a source of comfort to the bereaved. Nevertheless, there has been limited empirical investigation of this phenomenon, and consequently mental health professionals feel ill-equipped to support those who disclose them. Aims To map the phenomenology of ADCs, and identify covariates and effects upon the recipient. Method We conducted an online mixed-methods survey comprising 194 items about all aspects of ADCs. A purposive sample of 1004 respondents across three language groups (English, French and Spanish) completed the survey. Results The most common form of ADC was during sleep, but large numbers of cases involved sensory modalities of touch, sight, hearing, smell and sense of presence that externalised the phenomenon for the recipient. Variations in incidence with participant gender and language group suggest a psychosocial component. ADCs were typically regarded by the participant as deeply meaningful and comforting. Respondents reported significant increases in their sense of spirituality, but not religiosity. Conclusions ADCs are a common feature of bereavement that occur unexpectedly, and are independent of any underlying pathology or psychological need. For the person experiencing the hallucination, they are important and meaningful events that they interpret in terms of continuing bonds with the deceased. This adaptive outcome may be stymied where mental health professionals trivialise or pathologise disclosures about ADCs.

Hypertension is a major public health concern and poses a significant risk for sudden cardiac death (SCD). However, the characterisation of human tissues tends to be macroscopic, with little appreciation for the quantification of the pathological remodelling responsible for the advancement of the disease. While the components of hypertensive remodelling are well established, the timeline and comparative quantification of pathological changes in hypertension have not been shown before. Here, we sought to identify the phasing of cardiac remodelling with hypertension using post-mortem tissue from SCD patients with early and advanced hypertensive heart disease (HHD). In order to study and quantify the progression of phenotypic changes, human specimens were contrasted to a well-described angiotensin-II-mediated hypertensive mouse model. While cardiomyocyte hypertrophy is an early adaptive response in the mouse that stabilises in established hypertension and declines as the disease progresses, this finding did not translate to the human setting. In contrast, optimising fibrosis quantification methods and applying them to each setting identified perivascular fibrosis as the prevailing possible cause for overall disease progression. Indeed, assessing myocardial inflammation highlights CD45+ inflammatory cell infiltration that precedes fibrosis and is an early-phase event in response to elevated arterial pressures that may underscore perivascular remodelling. Along with aetiology insight, we highlight cross-species comparison for quantification of cardiac remodelling in human hypertension. As such, this platform could assist with the development of therapies specific to the disease phase rather than targeting global components of hypertension, such as blood pressure lowering.

The Asian Pacific Society of Cardiology convened a consensus statement panel for optimising cardiovascular (CV) outcomes in type 2 diabetes, and reviewed the current literature. Relevant articles were appraised using the Grading of Recommendations, Assessment, Development and Evaluation system, and consensus statements were developed in two meetings and were confirmed through online voting. The consensus statements indicated that lifestyle interventions must be emphasised for patients with prediabetes, and optimal glucose control should be encouraged when possible. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are recommended for patients with chronic kidney disease with adequate renal function, and for patients with heart failure with reduced ejection fraction. In addition to SGLT2i, glucagon-like peptide-1 receptor agonists are recommended for patients at high risk of CV events. A blood pressure target below 140/90 mmHg is generally recommended for patients with type 2 diabetes. Antiplatelet therapy is recommended for secondary prevention in patients with atherosclerotic CV disease.