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Background: Children with intellectual and developmental disabilities are at a higher risk of developing dental caries. Few scoping reviews have been conducted in India to understand their issues. We aimed to summarise the distribution and risk factors of dental caries among children and adolescents with intellectual disabilities in India. Methods: A scoping review was conducted based on the Arksey O Malley framework. Quality assessment of studies, descriptive and thematic analyses were also conducted. Results: We charted, collated, and summarised from four databases. Thirty-one studies met the study criteria consisting of children and adolescents with intellectual disabilities. Median caries prevalence was 70%, decayed missing and fIlled permenant teeth (DMFT) was 2.4, decayed missing and filled decidous teeth (dmft) was 2.36, and DMFS was 3.7. Major determinants were the severity of disability, socioeconomic status and parents' education. Oral care and dental visits were inadequate. Conclusion: Further exploration is required to improve access and reduce caries experience and prevalence among children with intellectual and developmental disabilities in India.

IntroductionT-cell receptors (TCRs) play a critical role in the immune response by recognizing specific ligand peptides presented by major histocompatibility complex (MHC) molecules. Accurate prediction of peptide binding to TCRs is essential for advancing immunotherapy, vaccine design, and understanding mechanisms of autoimmune disorders.MethodsThis study presents a theoretical approach that explores the impact of feature selection techniques on enhancing the predictive accuracy of peptide binding models tailored for specific TCRs. To evaluate our approach across different TCR systems, we utilized a dataset that includes peptide libraries tested against three distinct murine TCRs. A broad range of physicochemical properties, including amino acid composition, dipeptide composition, and tripeptide features, were integrated into the machine learning-based feature selection framework to identify key properties contributing to binding affinity.ResultsOur analysis reveals that leveraging optimized feature subsets not only simplifies the model complexity but also enhances predictive performance, enabling more precise identification of TCR peptide interactions. The results of our feature selection method are consistent with findings from hybrid approaches that utilize both sequence and structural data as input as well as experimental data.DiscussionOur theoretical approach highlights the role of feature selection in peptide-TCR interactions, providing a quantitative tool for uncovering the molecular mechanisms of the T-cell response and assisting in the design of more advanced targeted therapeutics.

Abstract The Addictions Neuroclinical Assessment (ANA) is a neurobiologically-informed framework designed to understand the etiology and heterogeneity of Alcohol Use Disorder (AUD). Previous studies validated the three neurofunctional domains of ANA: Incentive Salience (IS), Negative Emotionality (NE) and Executive Function (EF) using secondary data. The present cross-sectional observational study assessed these domains in an independent, prospective clinical sample. Adults across the drinking spectrum (N = 300) completed the ANA battery, a standardized collection of behavioral tasks and self-report assessments. Factor analyses were used to identify latent factors underlying each domain. Associations between identified domain factors were evaluated using structural equation models. Receiver operating characteristics analyses were used to determine factors with the strongest ability to classify individuals with problematic drinking and AUD. We found (1) two factors underlie the IS domain: alcohol motivation and alcohol insensitivity. (2) Three factors were identified for the NE domain: internalizing, externalizing, and psychological strength. (3) Five factors were found for the EF domain: inhibitory control, working memory, rumination, interoception, and impulsivity. (4) These ten factors showed varying degrees of cross-correlations, with alcohol motivation, internalizing, and impulsivity exhibiting the strongest correlations. (5) Alcohol motivation, alcohol insensitivity, and impulsivity showed the greatest ability in classifying individuals with problematic drinking and AUD. Thus, the present study identified unique factors underlying each ANA domain assessed using a standardized assessment battery. These results revealed additional dimensionality to the ANA domains, bringing together different constructs from the field into a single cohesive framework and advancing the field of addiction phenotyping. Future work will focus on identifying neurobiological correlates and identifying AUD subtypes based on these factors.

Measures of physical growth, such as weight and height have long been the predominant outcomes for monitoring child health and evaluating interventional outcomes in public health studies, including those that may impact neurodevelopment. While physical growth generally reflects overall health and nutritional status, it lacks sensitivity and specificity to brain growth and developing cognitive skills and abilities. Psychometric tools, e.g., the Bayley Scales of Infant and Toddler Development, may afford more direct assessment of cognitive development but they require language translation, cultural adaptation, and population norming. Further, they are not always reliable predictors of future outcomes when assessed within the first 12–18 months of a child’s life. Neuroimaging may provide more objective, sensitive, and predictive measures of neurodevelopment but tools such as magnetic resonance (MR) imaging are not readily available in many low and middle-income countries (LMICs). MRI systems that operate at lower magnetic fields (< 100mT) may offer increased accessibility, but their use for global health studies remains nascent. The UNITY project is envisaged as a global partnership to advance neuroimaging in global health studies. Here we describe the UNITY project, its goals, methods, operating procedures, and expected outcomes in characterizing neurodevelopment in sub-Saharan Africa and South Asia.

Summary: Cancer cell populations comprise phenotypes distributed among the epithelial-mesenchymal (E-M) spectrum. However, it remains unclear which population-level processes give rise to the observed experimental distribution and dynamical changes in E-M heterogeneity, including (1) differential growth, (2) cell-state switching, and (3) population density-dependent growth or state-transition rates. Here, we analyze the necessity of these three processes in explaining the dynamics of E-M population distributions as observed in PMC42-LA and HCC38 breast cancer cells. We find that, while cell-state transition is necessary to reproduce experimental observations of dynamical changes in E-M fractions, including density-dependent growth interactions (cooperation or suppression) better explains the data. Further, our models predict that treatment of HCC38 cells with transforming growth factor β (TGF-β) signaling and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/3) inhibitors enhances the rate of mesenchymal-epithelial transition (MET) instead of lowering that of E-M transition (EMT). Overall, our study identifies the population-level processes shaping the dynamics of spontaneous E-M heterogeneity in breast cancer cells.

Summary: The epithelial-to-mesenchymal transition (EMT) provides crucial insights into the metastatic process and possesses prognostic value within the cancer context. Here, we present COMET, an R package for inferring EMT trajectories and inter-state transition rates from single-cell RNA sequencing data. We describe steps for finding the optimal number of EMT genes for a specific context, estimating EMT-related trajectories, optimal fitting of continuous-time Markov chain to inferred trajectories, and estimating inter-state transition rates. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Molecular mechanisms based on photo-physical processes involving dietary carotenoids, their radicals, and the role of oxygen are discussed and used to suggest explanations of the poorly understood and often contradictory results related to mainly skin and vision. Differing and conflicting efficiencies of singlet oxygen reactions with carotenoids of biological importance are discussed in environments from ‘simple’ organic solvents to single He La cells. A range of free radical reactions with carotenoids, and the corresponding radicals of the carotenoids themselves, are compared and used to explain the switch from beneficial to deleterious processes involving dietary carotenoids and to unravel their differing functions; of particular interest is a possible role for vitamin C.

We report the fabrication and electrical characterization of single-hole transistors (SHTs), in which a Ge spherical quantum dot (QD) weakly couples to self-aligned electrodes via self-organized tunnel barriers of Si3N4. A combination of lithographic patterning, sidewall spacers, and self-assembled growth was used for fabrication. The core experimental approach is based on the selective oxidation of poly-SiGe spacer islands located at the specially designed included-angle locations of Si3N4/Si-trenches. By adjusting processing times for conformal deposition, etch back and thermal oxidation, good tunability in the Ge QD size and its tunnel-barrier widths were controllably achieved. Each Ge QD is electrically addressable via self-aligned Si gate and reservoirs, thus offering an effective building block for implementing single-charge devices.

Objective Quality of life (QoL) is inversely associated with alcohol misuse and is a key measure by which recovery from alcohol use disorder (AUD) might be assessed. Yet, the determinants of QoL are scarcely known. The authors examined three ways through which demographic characteristics, familial and early life factors, and psychopathology conferred risks for QoL, including unique direct effects, developmental pathways, and clinical risk Profiles. Methods Cross‐sectional data from 1095 adults (50.4% without AUD; 49.6% with AUD) who participated in the NIAAA Natural History Protocol from January 2015 to March 2022 were analyzed. Multivariable regressions, path analysis, and latent Profile analysis were conducted. Results AUD was uniquely associated with lower QoL, and adverse effects of child maltreatment history and psychopathology symptoms on QoL were of similar or larger magnitudes. Mediation analysis indicated family history of AUD and child maltreatment history were indirectly associated with lower QoL through higher attention‐deficit/hyperactivity disorder symptoms, higher depressive symptoms, and positive AUD diagnosis. Latent Profile analysis of an enriched set of clinical characteristics identified four latent Profiles capturing the full range of alcohol use behavior. Latent Profiles with greater severity of familial and early life factors, psychopathology, and problematic drinking showed dose‐response associations with lower levels of physical, psychological, social, and environment QoL. Conclusions A constellation of developmental and clinical characteristics disproportionately affects individuals with AUD and is negatively associated with QoL domains. To improve QoL, prevention and intervention need to target multiple factors, including history of child maltreatment, comorbid psychopathology, and problematic drinking itself.

T cell receptor (TCR)-peptide-major histocompatibility complex (pMHC) interactions play a vital role in initiating immune responses against pathogens, and the specificity of TCRpMHC interactions is crucial for developing optimized therapeutic strategies. The advent of high-throughput immunological and structural evaluation of TCR and pMHC has provided an abundance of data for computational approaches that aim to predict favorable TCR-pMHC interactions. Current models are constructed using information on protein sequence, structures, or a combination of both, and utilize a variety of statistical learning-based approaches for identifying the rules governing specificity. This review examines the current theoretical, computational, and deep learning approaches for identifying TCR-pMHC recognition pairs, placing emphasis on each method’s mathematical approach, predictive performance, and limitations.

Therapeutic Area: ASCVD /CVD Risk Reduction Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels. Currently, few treatments effectively lower LDL-C levels in pediatric patients with HoFH. Here, we report the efficacy and safety of evinacumab, a monoclonal antibody inhibitor of angiopoietin-like 3, in pediatric patients with HoFH. Methods: This is a three-part, open-label study (NCT04233918); Part B results are reported here. Part B enrolled 14 patients with HoFH 5–11 years old with LDL-C >130 mg/dL on optimized lipid-lowering therapy, including apheresis and lomitapide. All patients received intravenous evinacumab 15 mg/kg every 4 weeks. Results: All 14 patients completed Part B. Evinacumab treatment reduced mean (standard deviation) LDL-C from 263.7 (91.0) mg/dL at baseline to 131.8 (109.8) mg/dL at Week 24, with a mean (standard error [SE]) percent reduction of −48.3% (10.4%). Mean (SE) reductions in apolipoprotein B (−41.3% [9.0%]), non-high-density lipoprotein cholesterol (−48.9% [9.8%]), and total cholesterol (−49.1% [8.1%]) were also observed. Furthermore, percent LDL-C reduction observed at Week 24 from baseline based on the baseline LDL-C values or the presence of lomitapide treatment are presented in a Table. Additionally, the percent change from baseline in Lp(a) at Week 24 according to baseline apheresis status (Yes vs No) was similar: −43.7% (1.6%) versus −32.7% (1.4%), respectively. Treatment-emergent adverse events (TEAEs) occurred in 10 (71.4%) patients; no deaths or treatment discontinuations due to TEAEs were reported. Conclusions: Evinacumab substantially reduced LDL-C levels and other key atherogenic lipid parameters in pediatric patients with HoFH additive to any pre-existing treatment (including apheresis and lomitapide). Evinacumab was generally well-tolerated.

Global research activities have been driven by the quest to develop and characterize novel materials for technological advancements. The total scattering pair distribution function (TSPDF) is a powerful and versatile characterization technique for examining the structural details of diverse complex materials including liquid, amorphous, disordered crystalline, and nanostructured materials. Thus, it is critical to keep track of research progress, identify research gaps, and future research directions of the application of the TSPDF technique in materials development and discovery. In this work, a bibliometric analysis of literature regarding the TSPDF technique between 2000 and 2021 was conducted using datasets retrieved from the Web of Science database. The research trends based on publication outputs, research subject distribution, co-authorships among institutions, countries/regions, co-citation of referenced sources, and keyword co-occurrence are evaluated and discussed herein. The impact of the TSPDF technique is projected to increase due to its importance in probing emerging functional materials, and the advances in specialized facilities and instrumentation among the scientific communities engaged with it. Finally, current and emerging research hotspots related to TSPDF technique such as catalysis, computer modeling and simulation, pharmaceutics, machine learning, hydrogen storage, battery materials, and layered structured materials are also identified and discussed.

Summary: The Epithelial-to-Mesenchymal Transition (EMT) is a hallmark of cancer metastasis and morbidity. EMT is a non-binary process, and cells can be stably arrested en route to EMT in an intermediate hybrid state associated with enhanced tumor aggressiveness and worse patient outcomes. Understanding EMT progression in detail will provide fundamental insights into the mechanisms underlying metastasis. Despite increasingly available single-cell RNA sequencing (scRNA-seq) data that enable in-depth analyses of EMT at the single-cell resolution, current inferential approaches are limited to bulk microarray data. There is thus a great need for computational frameworks to systematically infer and predict the timing and distribution of EMT-related states at single-cell resolution. Here, we develop a computational framework for reliable inference and prediction of EMT-related trajectories from scRNA-seq data. Our model can be utilized across a variety of applications to predict the timing and distribution of EMT from single-cell sequencing data.

The early abstinence period is a crucial phase in alcohol use disorder (AUD) in which patients have to find a new equilibrium and may start recovery, or conversely, relapse. However, the changes in brain functions during this key period are still largely unknown. We set out to study longitudinal changes in large-scale brain networks during the early abstinence period using resting-state scans. We scanned AUD patients twice in a well-controlled inpatient setting, with the first scan taking place shortly after admission and the second scan 4 weeks (±9 days) later near the end of the treatment period. We studied 37 AUD patients (22 males) and 27 healthy controls (16 males). We focused on three networks that are affected in AUD and underly core symptom dimensions in this disorder: the frontoparietal networks (left and right FPN) and default mode network (DMN). Both the whole brain and within network connectivity of these networks were studied using dual regression. Finally, we explored correlations between these brain networks and various neuropsychological and behavioral measures. In contrast to the controls (Z = −1.081, p = 0.280), the AUD patients showed a decrease in within left FPN connectivity (Z = −2.029, p = 0.042). However, these results did not survive a strict Bonferroni correction. The decrease in left FPN connectivity during the early abstinence period in AUD may reflect an initially upregulated FPN, which recovers to a lower resting-state connectivity level during subsequent weeks of abstinence. The AUD patients showed a trend for a positive association between the change in left FPN connectivity and trait anxiety (rs = 0.303, p = 0.068), and a trend for a negative association between the change in left FPN connectivity and delay discounting (rs = −0.283, p = 0.089) (uncorrected for multiple comparisons). This suggests that the FPN might be involved in top-down control of impulsivity and anxiety, which are important risk factors for relapse. Although there were no statistically significant results (after multiple comparison correction), our preliminary findings encourage further research into the dynamic neuroadaptations during the clinically crucial early abstinence period and could inform future study designs.

Abstract The commentary by Dr. Labruyere on the article by Kuo et al. (J Neuroeng Rehabil. 2021; 18:174) posits that randomized trials evaluating the comparative efficacy of robotic devices for patients with neurological injury may not be needed. The primary argument is that researchers and clinicians do not know how to optimize training parameters to maximize the benefits of this therapy, and studies vary in how they deliver robotic-assisted training. While I concur with the suggestion that additional trials using robotic devices as therapeutic tools are not warranted, an alternative hypothesis is that future studies will yield similar equivocal results regardless of the training parameters used. Attempts are made to detail arguments supporting this premise, including the notion that the original rationale for providing robotic-assisted walking training, particularly with exoskeletal devices, was flawed and that the design of some of the more commonly used devices places inherent limitations on the ability to maximize neuromuscular demands during training. While these devices arrived nearly 20 years ago amid substantial enthusiasm, we have since learned valuable lessons from robotic-assisted and other rehabilitation studies on some of the critical parameters that influence neuromuscular and cardiovascular activity during locomotor training, and different strategies are now needed to optimize rehabilitation outcomes.

The failure of cancer treatments, including immunotherapy, continues to be a major obstacle in preventing durable remission. This failure often results from tumor evolution, both genotypic and phenotypic, away from sensitive cell states. Here, we propose a mathematical framework for studying the dynamics of adaptive immune evasion that tracks the number of tumor-associated antigens available for immune targeting. We solve for the unique optimal cancer evasion strategy using stochastic dynamic programming and demonstrate that this policy results in increased cancer evasion rates compared to a passive, fixed strategy. Our foundational model relates the likelihood and temporal dynamics of cancer evasion to features of the immune microenvironment, where tumor immunogenicity reflects a balance between cancer adaptation and host recognition. In contrast with a passive strategy, optimally adaptive evaders navigating varying selective environments result in substantially heterogeneous post-escape tumor antigenicity, giving rise to immunogenically hot and cold tumors.

Abstract Aims In the EMPA‐REG OUTCOME trial, empagliflozin reduced risk of death from heart failure (HF) or hospitalization for heart failure (HHF) versus placebo in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease. We evaluated post hoc the degree to which covariates mediated the effects of empagliflozin on HHF or HF death. Methods and results A mediator had to fulfil the following criteria: (i) affected by active treatment, (ii) associated with the outcome, and finally (iii) adjustment for it results in a reduced treatment effect compared with unadjusted analysis. Potential mediators were calculated as change from baseline or updated mean and evaluated in univariable analyses as time‐dependent covariates in Cox regression of time to HHF or HF death; those with the largest mediating effects were then included in a multivariable analysis. Increases in heart rate, log urine albumin‐to‐creatinine ratio (UACR), waist circumference, and uric acid were associated with increased risk of HHF or HF death; increases in high‐density lipoprotein cholesterol, estimated glomerular filtration rate, haematocrit, haemoglobin, and albumin were associated with reduced risk of HHF or HF death. In univariable analyses, change from baseline in haematocrit, haemoglobin, albumin, uric acid, and logUACR mediated 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin versus placebo, respectively. Multivariable analysis including haemoglobin, logUACR, and uric acid mediated 85% of risk reduction with similar results when updated means were evaluated. Conclusions Changes in haematocrit and haemoglobin were the most important mediators of the reduction in HHF and death from HF in patients with T2DM and established CV disease treated with empagliflozin. Albumin, uric acid, and logUACR had smaller mediating effects in this population.

Background Blockade of the lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, and target engagement of MEDI6570, a high‐affinity monoclonal blocking antibody to LOX‐1. Methods and Results This phase 1, first‐in‐human, placebo‐controlled study (NCT03654313) randomized 88 patients with type 2 diabetes to receive single ascending doses (10, 30, 90, 250, or 500 mg) or multiple ascending doses (90, 150, or 250 mg once monthly for 3 months) of MEDI6570 or placebo. Primary end point was safety; secondary and exploratory end points included pharmacokinetics, immunogenicity, free soluble LOX‐1 levels, and change in coronary plaque volume. Mean age was 57.6/58.1 years in the single ascending doses/multiple ascending doses groups, 31.3%/62.5% were female, and mean type 2 diabetes duration was 9.7/8.7 years. Incidence of adverse events was similar among cohorts. MEDI6570 exhibited nonlinear pharmacokinetics, with terminal half‐life increasing from 4.6 days (30 mg) to 11.2 days (500 mg), consistent with target‐mediated drug disposition. Dose‐dependent reductions in mean soluble LOX‐1 levels from baseline were observed (>66% at 4 weeks and 71.61–82.96% at 10 weeks in the single ascending doses and multiple ascending doses groups, respectively). After 3 doses, MEDI6570 was associated with nonsignificant regression of noncalcified plaque volume versus placebo (−13.45 mm3 versus −8.25 mm3). Conclusions MEDI6570 was well tolerated and demonstrated dose‐dependent soluble LOX‐1 suppression and a pharmacokinetic profile consistent with once‐monthly dosing. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT03654313.

Advances in genetics has led to a better understanding of both genetic and environmental contributions to psychiatric mental health disorders. But psychiatric genetics research is predominantly Eurocentric, and individuals of non-European ancestry continue to be significantly underrepresented in research studies with potential to worsen existing mental health disparities. The objective of this study was to examine factors associated with genetic study participation in a schizophrenia sample. The study sample was extracted from the Clinical Antipsychotics Trial of Intervention Effectiveness (CATIE) schizophrenia study which enrolled 1493 patients with chronic schizophrenia between the ages of 18-65 years and incorporated an optional genetic sub-study. Using a logistic regression model (N = 1249), we examined sociodemographic and clinical variables that were independently associated with the outcome i.e., participation in the genetic sub-study. The genetic sub-study had a lower proportion of Black (30% in genetic vs 40% in CATIE overall) and other race (4% vs 6%) participants. Increased severity of psychopathology symptoms (odds ratio [OR] = 0.78, p = 0.004) decreased the odds whereas better reasoning scores (OR = 1.16, p = 0.036) increased the odds of genetic study participation. Compared to Black participants, White participants were significantly more likely to participate in the genetic sub-study (OR = 1.43, p = 0.009). Clinical factors in addition to race significantly impact genetic study participation of individuals with chronic schizophrenia. Our findings highlight the need for future research that examines the interactive effects of race and clinical factors such as symptom severity on psychiatrically ill individuals' choice to participate in genetics studies and to identify targeted strategies to increase equitable representation in psychiatric genetics research.

Objective: Assess potential impacts of the COVID-19 pandemic on a subset of Post-9/11 U.S. Veterans included in a study of post-traumatic epilepsy (PTE). Methods: Two measures were added to a structured health interview for Veterans during temporary pandemic research shutdown: a validated health questionnaire [1] previously completed by survey, and a semi-structured instrument developed to assess whether pandemic conditions affected responses to the health questionnaire and identify unique impacts. Interviews were conducted between August 2020 – February 2021. Scaled items were calculated and t-tests used to compare results. Open-ended items were coded using thematic analyses. Results: Veterans identified eight major areas of impact with negative and positive impacts: mental health, family, social, work/employment, access to resources, physical health, finances, and education. Innovation: The temporary shut-down of a large health study for Post-9/11 Veterans provided an opportunity to devise an instrument to assess COVID-19's impact on health and well-being. The instrument was accepted as of the first Veteran instrument in a pandemic SDOH research repository [2], and is being used in other studies. Conclusion: This study highlights the need to assess and understand interrelated relationships of factors impacting health and well-being, especially as COVID-19 moves from pandemic to endemic with reverberating effects across multiple social determinants of health (SDOH).

Abstract Aims Despite substantial improvements over the last three decades, heart failure (HF) remains associated with a poor prognosis. The sodium‐glucose co‐transporter‐2 inhibitor empagliflozin demonstrated significant reductions of HF hospitalization in patients with HF independent of the presence or absence of type 2 diabetes mellitus in the EMPEROR‐Reduced trial and cardiovascular mortality in the EMPA‐REG OUTCOME trial. To further elucidate the mechanisms behind these positive outcomes, this study aims to determine the effects of empagliflozin treatment on cardiac energy metabolism and physiology using magnetic resonance spectroscopy (MRS) and cardiovascular magnetic resonance (CMR). Methods and results The EMPA‐VISION trial is a double‐blind, randomized, placebo‐controlled, mechanistic study. A maximum of 86 patients with HF with reduced ejection fraction (n = 43, Cohort A) or preserved ejection fraction (n = 43, Cohort B), with or without type 2 diabetes mellitus, will be enrolled. Participants will be randomized 1:1 to receive either 10 mg of empagliflozin or placebo for 12 weeks. Eligible patients will undergo cardiovascular magnetic resonance, resting and dobutamine stress MRS, echocardiograms, cardiopulmonary exercise tests, serum metabolomics, and quality of life questionnaires at baseline and after 12 weeks. The primary endpoint will be the change in resting phosphocreatine‐to‐adenosine triphosphate ratio, as measured by 31Phosphorus‐MRS. Conclusions EMPA‐VISION is the first clinical trial assessing the effects of empagliflozin treatment on cardiac energy metabolism in human subjects in vivo. The results will shed light on the mechanistic action of empagliflozin in patients with HF and help to explain the results of the safety and efficacy outcome trials (EMPEROR‐Reduced and EMPEROR‐Preserved).

Objective Interindividual variation in responses to alcohol is substantial, posing challenges for medical management and for understanding the biological underpinnings of alcohol use disorders (AUD). It is important to understand whether diverse alcohol responses such as sedation, which is predictive of risk and partly heritable, occur concurrently or independently from responses such as blackouts and withdrawal. We hypothesized that latent factors accounting for sources of variance in diverse alcohol response phenotypes could be identified in a large, deeply phenotyped sample of patients with AUD. Methods We factor analyzed 17 alcohol response related items from the Alcohol Dependence Scale (ADS) in 938 individuals diagnosed with AUD via structured clinical interviews. Demographic, genetic, and clinical characteristics were tested as predictors of the latent factors by multiple indicators, multiple causes analysis. Results The final factor solution included three alcohol response factors: Physical Symptoms, Perceptual Disturbances, and Neurobiological Effects. Both gender and genetic ancestry were identified as variables influencing alcohol response. Major depressive disorder positively predicted physical symptoms and aggression negatively predicted physical symptoms. Barratt's Impulsivity Scale total score predicted the Physical and Perceptual domains. Family history, average drinks per drinking day, and negative urgency (an impulsivity measure) predicted all three domains. Conclusions Diverse items from the ADS concurrently load onto three correlated alcohol response factors rather than loading independently. Genetic ancestry and clinical characteristics predicted the severity of items that define the alcohol response factors even after accounting for degree of alcohol consumption. Co‐occurring phenotypes point towards an underlying shared physiology of diverse alcohol responses.

Calciphylaxis, also known as calcific uremic arteriolopathy, is a condition most commonly seen in patients with End-stage Renal Disease. The pathophysiology of the condition is related to an elevated calcium-phosphate product. It associated with extensive calcification, especially of the media of arterioles. It most commonly presents with skin manifestations, especially in the abdomen. However, when it occurs in the breast, it can mimic an advanced breast malignancy. We report a case of a 34-year-old female who presented with an extensive lesion to the breast, initially thought to be a long-neglected breast carcinoma. However, it was ultimately diagnosed as calciphylaxis of the breast, and radiologic imaging (particularly ultrasound and mammography) were crucial in making the diagnosis. We make the case of the importance of radiologic imaging in diagnosing this condition.

Abstract Aims Heart failure (HF) and type 2 diabetes (T2D), common co‐morbidities, translate into worse patient prognoses and higher direct costs than for either condition alone. Empagliflozin has been shown to markedly reduce cardiovascular (CV) deaths and HF hospitalizations (HHF) in HF patients with T2D. This study evaluated the lifetime cost‐effectiveness of supplementing standard of care (SoC) with empagliflozin, relative to SoC alone, in HF patients with T2D from the UK payer perspective. Methods and results An existing discrete‐event simulation model was adapted for the economic evaluation. Risk equations developed from time‐dependent parametric survival analyses using patient‐level HF subpopulation data from the EMPA‐REG OUTCOME trial were employed to predict CV and renal events. Non‐CV death, utility weights, and costs were drawn from UK sources. Quality‐adjusted life years (QALYs) and costs were discounted at 3.5% per annum. Relative to SoC, empagliflozin with SoC yielded fewer first HHF, recurrent HHF, CV death, and non‐fatal myocardial infarction but more non‐fatal stroke events. Empagliflozin with SoC vs. SoC alone was associated with increased average life expectancy (10.80 vs. 9.59 LYs) and quality of life (6.27 vs. 5.62 QALYs), though at higher lifetime cost (£18 197 vs. £16 829) per person, resulting in an incremental cost‐effectiveness ratio of £2093 per QALY. The probability of empagliflozin being cost‐effective in the HF subpopulation at a £20 000 per QALY willingness‐to‐pay threshold was 91%. Conclusions This analysis suggests that adding empagliflozin to SoC in HF patients with T2D constitutes a cost‐effective use of UK healthcare resources and may provide long‐term health benefits to patients.

Abstract The leaf phenology (i.e. the seasonality of leaf amount and leaf demography) of ecosystems can be characterized through the use of Earth observation data using a variety of different approaches. The most common approach is to derive time series of vegetation indices (VIs) which are related to the temporal evolution of FPAR, LAI and GPP or alternatively used to derive phenology metrics that quantify the growing season. The product presented here shows a map of average ‘amplitude’ (i.e. maximum minus minimum) of annual cycles observed in MODIS‐derived NDVI and EVI from 2000 to 2013 for Meso‐ and South America. It is a robust determination of the amplitude of annual cycles of vegetation greenness derived from a Lomb–Scargle spectral analysis of unevenly spaced data. VI time series pre‐processing was used to eliminate measurement outliers, and the outputs of the spectral analysis were screened for statistically significant annual signals. Amplitude maps provide an indication of net ecosystem phenology since the satellite observations integrate the greenness variations across the plant individuals within each pixel. The average amplitude values can be interpreted as indicating the degree to which the leaf life cycles of individual plants and species are synchronized. Areas without statistically significant annual variations in greenness may still consist of individuals that show a well‐defined annual leaf phenology. In such cases, the timing of the phenology events will vary strongly within the year between individuals. Alternatively, such areas may consist mainly of plants with leaf turnover strategies that maintain a constant canopy of leaves of different ages. Comparison with in situ observations confirms our interpretation of the average amplitude measure. VI amplitude interpreted as leaf life cycle synchrony can support model evaluation by informing on the likely leaf turn over rates and seasonal variation in ecosystem leaf age distribution.

Domestic cats (Felis catus) are amongst the most destructive invasive vertebrates globally, depredating billions of native animals annually. The size and seasonal variation of their geographical “footprint” is key to understanding their effects on wildlife, particularly if they live near conservation areas. Here we report the first GPS-tracking studies of free-roaming owned cats in the city of Cape Town, South Africa. A total of 23 cats was tracked (14 cats in summer, 9 in winter) using miniature (22 g) GPS locators in 2010–2011. In summer, all cats living on the urban-edge (UE: n = 7) made extensive use of protected areas, while only one of seven urban (U) cats (>150 m from the edge) did so. In winter two of four UE and two of five U cats entered protected areas. Home ranges (95% kernel density estimates) were significantly larger in summer (3.00 ± 1.23 ha) than winter (0.87 ± 0.25 ha) and cats ventured further from their homes in summer (maximum 849 m) than in winter (max 298 m). The predation risk posed by caracal (Caracal caracal) may limit the time cats spend in protected areas, but our results suggest that cat buffers around conservation areas should be at least ~600 m wide to reduce impacts to native fauna.

Hyperglycemia is an undisputed epidemiological risk factor for microvascular complications in both type 1 and type 2 diabetes, integral in their causal pathways. Importantly, interventions that reduce the hyperglycemic burden in patients with either type of diabetes reduce the risk of microvascular complications (e.g., retinopathy, nephropathy, neuropathy). Hence, for microvascular risk, hyperglycemia is a proven risk factor and a proven treatment target, as reflected by treatment recommendations and guidelines across most scientific societies world-wide. However, although reducing the hyperglycemic burden to reduce microvascular risk remains a cornerstone of care for patients with type 2 diabetes, this therapeutic imperative does not apply to cardiovascular risk mitigation. This latter aspect is important in the context of interpreting therapeutic impact of treating hyperglycemia on risk for macrovascular complications in patients with type 2 diabetes. This letter, in response to a previous paper, discuss how modest differential glucose control contribute little if anything to the results observed of contemporary cardiovascular outcome trials in type 2 diabetes.

Sleep disturbances are common among individuals with alcohol use disorder (AUD) and may not resolve completely with short-term abstinence from alcohol, potentially contributing to relapse to drinking. The endocannabinoid system (ECS) is associated with both sleep and alcohol consumption, and genetic variation in the ECS may underlie sleep-related phenotypes among individuals with AUD. In this study, we explored the influence of genetic variants in the ECS (Cannabinoid receptor 1/CNR1: rs806368, rs1049353, rs6454674, rs2180619, and Fatty Acid Amide Hydrolase/FAAH rs324420) on sleep quality in individuals with AUD (N = 497) and controls without AUD (N = 389). We assessed subjective sleep quality (from the Pittsburgh Sleep Quality Index/PSQI) for both groups at baseline and objective sleep efficiency and duration (using actigraphy) in a subset of individuals with AUD at baseline and after 4 weeks of inpatient treatment. We observed a dose-dependent relationship between alcohol consumption and sleep quality in both AUD and control groups. Sleep disturbance, a subscale measure in PSQI, differed significantly among CNR1 rs6454674 genotypes in both AUD (p = 0.015) and controls (p = 0.016). Only among controls, neuroticism personality scores mediated the relationship between genotype and sleep disturbance. Objective sleep measures (sleep efficiency, wake bouts and wake after sleep onset), differed significantly by CNR1 rs806368 genotype, both at baseline (p = 0.023, 0.029, 0.015, respectively) and at follow-up (p = 0.004, p = 0.006, p = 0.007, respectively), and by FAAH genotype for actigraphy recorded sleep duration at follow-up (p = 0.018). These relationships suggest a significant role of the ECS in alcohol-related sleep phenotypes.

Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate‐limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double‐blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment‐emergent adverse events that were similar to those of placebo. Dose‐dependent increases in high‐density lipoprotein cholesterol were observed with area under the concentration‐time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high‐density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non‐ATP‐binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low‐density lipoprotein particles by 41%, 88%, and 79% at the 80‐, 240‐, and 800‐mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high‐density lipoprotein cholesterol, endogenous apoA1, and non‐ATP‐binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low‐density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high‐density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601560.

Inflammatory breast cancer (IBC) is a highly aggressive breast cancer that metastasizes largely via tumor emboli, and has a 5-year survival rate of less than 30%. No unique genomic signature has yet been identified for IBC nor has any specific molecular therapeutic been developed to manage the disease. Thus, identifying gene expression signatures specific to IBC remains crucial. Here, we compare various gene lists that have been proposed as molecular footprints of IBC using different clinical samples as training and validation sets and using independent training algorithms, and determine their accuracy in identifying IBC samples in three independent datasets. We show that these gene lists have little to no mutual overlap, and have limited predictive accuracy in identifying IBC samples. Despite this inconsistency, single-sample gene set enrichment analysis (ssGSEA) of IBC samples correlate with their position on the epithelial-hybrid-mesenchymal spectrum. This positioning, together with ssGSEA scores, improves the accuracy of IBC identification across the three independent datasets. Finally, we observed that IBC samples robustly displayed a higher coefficient of variation in terms of EMT scores, as compared to non-IBC samples. Pending verification that this patient-to-patient variability extends to intratumor heterogeneity within a single patient, these results suggest that higher heterogeneity along the epithelial-hybrid-mesenchymal spectrum can be regarded to be a hallmark of IBC and a possibly useful biomarker.

Background Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA‐REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches. Methods and Results A total of 7020 patients with type 2 diabetes mellitus and established cardiovascular disease were treated with empagliflozin 10 or 25 mg (n=4687) or placebo (n=2333) on top of standard care. Cardio/kidney composite end points studied were: (1) cardiac or kidney death, kidney failure, hospitalization for heart failure, sustained decline in estimated glomerular filtration rate ≥40% from baseline, or sustained progression to macroalbuminuria; (2) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained estimated glomerular filtration rate decline ≥40% from baseline; and (3) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained doubling in serum creatinine from baseline. Cox regression using time‐to‐first‐event analysis and win ratio (WR) using hierarchical order of events were applied. Empagliflozin reduced the risk of all cardio/kidney composites. The results varied only slightly between Cox and WR (eg, composite 1: hazard ratio, 0.56 [95% CI, 0.49–0.64]; WR, 1.76 [95% CI, 1.53–2.02]. WR prioritizes events by clinical importance; in particular, all fatal events are evaluated, whereas Cox regression ignores deaths when preceded by nonfatal events. Of the 285 cardio/kidney deaths in the analysis, 44 to 56 (15%–20%), depending on the composite, occurred after a nonfatal event and were not evaluated in Cox regression but evaluated by the WR. Conclusions By considering the clinical relevance of different event types, the WR represents an appropriate method to complement the traditional time‐to‐first‐event analysis in cardio/kidney outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01131676.

African yam bean (AYB) is an underutilised legume indigenous to West and East Africa with nutritional content comparable to other commonly consumed legumes. The nutrient density of the crop makes it a viable food crop for ameliorating the challenges of malnutrition faced in many developing countries, via direct consumption or fortification and enrichment of less nutritious staples. This review summarises the current body of knowledge on the use of African yam bean as a viable enrichment and fortification crop. Proximate composition and nutritional quality of foods (breakfast diets, traditional foods, snacks and instant noodles) fortified, enriched and complemented with AYB were discussed. The phytochemical and antioxidant potential of the crop were also discussed. Future studies should focus more on awareness towards the deliberate commercialisation of the crop and elevation of its status into a widely - consumed food in all households across developing countries. Adequate experimental design for optimum quantity to be used in the enrichment and fortification of many staples to improve their acceptance among consumers should be put in place. Phytochemical extracts of the bean are also proposed for use in the development of functional foods to mitigate against many lifestyle diseases.

Domestic cats (Felis catus) have contributed to the extinction of indigenous species worldwide, but impacts in Africa are unstudied. We compare prey returned home from three questionnaire surveys (2009, 2010 and 2013/14) in Cape Town, South Africa, with footage from some of the same cats wearing animal-borne video cameras (KittyCams), to assess differences in actual predation vs. returns. Cape Town borders Table Mountain National Park (TMNP), so cats may prey on animals in a protected area. Urban edge (UE) and deep urban cats (DU) did not differ in predation rates, but the suite of species killed differed significantly. KittyCams revealed that most predation was nocturnal, and only 18% of prey recorded on video were returned home, thus cats kill 5.56 times more animals (averaged across all taxa) than returns data suggest. Reptiles constituted 50% of prey, but only 17% of returns; mammals constituted 24% of prey, but 54% of returns. Non-native species represented only 6% and 17% of animals killed by UE and DU cats, respectively, pointing to a high cost of cat predation for native fauna. Applying a correction factor of 5.56, the average domestic cat in Cape Town kills c. 90 (95% CI = 59, 123), animals.year−1. Thus, the approximately 300 000 domestic cats in Cape Town kill c. 27.5 million animals.year−1, and TMNP is likely to lose c. 203 500 animals to UE cats annually from within its boundaries. The scale of this predation necessitates conservation options to minimise impacts of cats on wildlife, particularly near protected areas.

The Epithelial–mesenchymal transition (EMT) is a cellular process implicated in embryonic development, wound healing, and pathological conditions such as cancer metastasis and fibrosis. Cancer cells undergoing EMT exhibit enhanced aggressive behavior characterized by drug resistance, tumor-initiation potential, and the ability to evade the immune system. Recent in silico, in vitro, and in vivo evidence indicates that EMT is not an all-or-none process; instead, cells can stably acquire one or more hybrid epithelial/mesenchymal (E/M) phenotypes which often can be more aggressive than purely E or M cell populations. Thus, the EMT status of cancer cells can prove to be a critical estimate of patient prognosis. Recent attempts have employed different transcriptomics signatures to quantify EMT status in cell lines and patient tumors. However, a comprehensive comparison of these methods, including their accuracy in identifying cells in the hybrid E/M phenotype(s), is lacking. Here, we compare three distinct metrics that score EMT on a continuum, based on the transcriptomics signature of individual samples. Our results demonstrate that these methods exhibit good concordance among themselves in quantifying the extent of EMT in a given sample. Moreover, scoring EMT using any of the three methods discerned that cells can undergo varying extents of EMT across tumor types. Separately, our analysis also identified tumor types with maximum variability in terms of EMT and associated an enrichment of hybrid E/M signatures in these samples. Moreover, we also found that the multinomial logistic regression (MLR)-based metric was capable of distinguishing between “pure” individual hybrid E/M vs. mixtures of E and M cells. Our results, thus, suggest that while any of the three methods can indicate a generic trend in the EMT status of a given cell, the MLR method has two additional advantages: (a) it uses a small number of predictors to calculate the EMT score and (b) it can predict from the transcriptomic signature of a population whether it is comprised of “pure” hybrid E/M cells at the single-cell level or is instead an ensemble of E and M cell subpopulations.

Abstract Background Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA® trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. Methods CARMELINA® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5–10.0% (48–86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA® was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. Results Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m2, and eGFR 55 ± 25 mL/min/1.73 m2. A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common. Conclusions CARMELINA® will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. Trial registration ClinicalTrials.gov identifier—NCT01897532; registered July 9, 2013

The encapsulation of bioactive-rich plant extracts is an effective method of preventing their damage or loss of activity during processing and storage. Here, the techno-functional properties of microcapsules developed from Moringa oleifera leaf powder (MoLP) extract (core) with maltodextrin (MD), gum Arabic (GA), and a combination (MDGA) (coatings) were assessed. The bulk and tap density were 0.177, 0.325 and 0.297 g/mL and 0.13, 0.295 and 0.259 g/mL for GA, MD and MDGA microcapsules, respectively. Flowability properties of microcapsules indicated an intermediate flow except for GA which had a poor flow. The moisture content of the microcapsules ranged from 1.47% to 1.77% with no significant differences (p > 0.05) observed. All the microcapsules had high water solubility (86.35% for GA to 98.74% for MD and 90.51% for MDGA). Thermogravimetric analyses revealed that encapsulation enhanced the thermal stability of the core material. The X-ray diffraction analysis revealed that the microcapsules and extracts have an amorphous nature, which was validated by the surface morphology analysis that showed amorphous, irregular, and flake-like attributes except for MDGA microcapsules which had slightly spherical and agglomerated surfaces. The Fourier Transform Infra-Red spectra of the microcapsules showed the presence of C-O and O-H aromatic rings as well as amine groups. New spectra were observed at 1177, 1382 and 1411 cm−1 for MDGA, MD and GA, respectively, after encapsulation, which connotes a slight modification in the chemical structural pattern after encapsulation. Storage stability tests (28 days at 4, 25 and 40 °C) showed that the microcapsules were most stable at 4 °C and the stability differs significantly (p ≤ 0.05) with coating material type and temperature with MDGA showing better storage stability than others. Altogether, the attributes of the MDGA microcapsules were comparatively better than either MD or GA alone. The present data, therefore, demonstrate an effective encapsulation process for MoLP extract that can serve as fortificants in processed food products where MoLP may be used.