AIMS: Pancreatic polypeptide (PP) is elevated in people with vascular risk factors such as type 2 diabetes or increased visceral fat. We investigated potential relationships between PP and microvascular and macrovascular complications of diabetes. MATERIALS AND METHODS: Animal study: Subcutaneous PP infusion for 4 weeks in high fat diet mouse model. Retinal mRNA submitted for Ingenuity Pathway Analysis. Human study: fasting PP measured in 1478 participants and vascular complications recorded over median 5.5 (IQR 4.9-5.8) years follow-up. RESULTS: Animal study: The retinal transcriptional response to PP was indicative of cellular stress and damage, and this footprint matched responses described in previously published studies of retinal disease. Of mechanistic importance the transcriptional landscape was consistent with upregulation of folliculin, a recently identified susceptibility gene for diabetic retinopathy. Human study: Adjusting for established risk factors, PP was associated with prevalent and incident clinically significant retinopathy (odds ratio (OR) 1.289 (1.107-1.501) p = 0.001; hazard ratio (HR) 1.259 (1.035-1.531) p = 0.0213), albuminuria (OR 1.277 (1.124-1.454), p = 0.0002; HR 1.608 (1.208-2.141) p = 0.0011), and macrovascular disease (OR 1.021 (1.006-1.037) p = 0.0068; HR 1.324 (1.089-1.61), p = 0.0049), in individuals with type 2 diabetes, and progression to diabetes in non-diabetic individuals (HR 1.402 (1.081-1.818), p = 0.0109). CONCLUSIONS: Elevated fasting PP is independently associated with vascular complications of diabetes and affects retinal pathways potentially influencing retinal neuronal survival. Our results suggest possible new roles for PP-fold peptides in the pathophysiology of diabetes complications and vascular risk stratification.
Diabetes Mellitus, Type 2 , Diabetic Angiopathies , Diabetic Retinopathy , Fasting , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/pathology , Humans , Male , Female , Middle Aged , Diabetic Angiopathies/etiology , Diabetic Angiopathies/epidemiology , Animals , Mice , Follow-Up Studies , Diabetic Retinopathy/etiology , Diabetic Retinopathy/epidemiology , Diabetic Retinopathy/pathology , Prognosis , Incidence , Biomarkers/analysis , Risk Factors , Aged
Quinoa downy mildew, caused by Peronospora variabilis, is the most devastating disease of quinoa globally. Rapid, sensitive diagnostic methods are needed to detect and quantify this pathogen in seeds and plant tissue. A hydrolysis probe-based quantitative real-time PCR (qPCR) assay including a competitive internal control was developed for P. variabilis detection. This assay could detect as low as 20 ag of DNA or approximately 25 internal transcribed spacer (ITS) copies per reaction with efficiencies ranging from 93.9 to 98.2%. No non-target amplification was observed when tested against DNA from other downy mildew pathogens and related oomycetes. Peronospora variabilis strains from multiple countries were detected using this assay. The assay was successfully applied to quantify the pathogen in quinoa seeds from a field trial conducted in Washington State. Downy mildew disease was recorded on all 14 genotypes with the genotypes 104.88 and 106.49 recording the highest area under the disease progress values (3,236 ± 303 SE and 2,851 ± 198, respectively) while J6 and Dutchess recorded the lowest (441 ± 107 and 409 ± 129, respectively). Seed washes obtained from field samples were subjected to the qPCR assay, and the pathogen was detected in all samples. The highest pathogen ITS copy number recorded with 106.49 (194,934 ± 38,171 SE), while the lowest was observed in Pasto (5,971 ± 1,435) and Riobamba (9,954 ± 4,243). This qPCR assay could lead to improved detection and quantification of P. variabilis as well as increased understanding of quinoa-P. variabilis interactions and epidemiology.
BACKGROUND: Asthma control assessment is based on impairment (current symptoms) and risk (exacerbation history). OBJECTIVE: To understand the extent of uncontrolled asthma, we assessed relationships between prescription fills for systemic corticosteroids (SCS) and short-acting ß2-agonists (SABA) as risk and impairment markers, respectively. METHODS: Annual SCS and SABA fills among US patients with asthma were evaluated by a retrospective analysis of IQVIA Longitudinal Access and Adjudication Data. Patient severity was assigned based on GINA step-therapy level. Exacerbations were evaluated by SCS fills within 12 months of a first asthma prescription fill. Uncontrolled asthma was defined as ≥2 SCS and/or ≥3 SABA fills annually. Individual patient relationships between SCS and SABA fills were assessed by Pearson's correlation coefficient. RESULTS: 4,506,527 patients were included: 15% had ≥2 SCS fills, 29% had ≥3 SABA fills, 37% fulfilled either or both criteria. If only SCS were assessed, 22% treated as mild-to-moderate and 27% as severe asthma would have been misclassified as controlled. If only SABA use was evaluated, 8% treated as mild-to-moderate and 11% as severe asthma would have been misclassified. Overall, 81% of uncontrolled asthma occurred in patients treated for mild-to-moderate disease. Among patients with ≥2 SCS fills, mean SABA fills were 2.9; the correlation between SCS and SABA fills per patient was significant but weak (r=0.18; p<0.001). CONCLUSION: High symptom burden and SCS exposures are not limited to severe asthma but are also characteristic in patients treated for mild-to-moderate disease. Both impairment and risk assessments are required to understand the full extent of uncontrolled asthma across disease severities.
The D2 dopamine receptor (DRD2) gene has garnered substantial attention as one of the most extensively studied genes across various neuropsychiatric disorders. Since its initial association with severe alcoholism in 1990, particularly through the identification of the DRD2 Taq A1 allele, numerous international investigations have been conducted to elucidate its role in different conditions. As of February 22, 2024, there are 5485 articles focusing on the DRD2 gene listed in PUBMED. There have been 120 meta-analyses with mixed results. In our opinion, the primary cause of negative reports regarding the association of various DRD2 gene polymorphisms is the inadequate screening of controls, not adequately eliminating many hidden reward deficiency syndrome behaviors. Moreover, pleiotropic effects of DRD2 variants have been identified in neuropsychologic, neurophysiologic, stress response, social stress defeat, maternal deprivation, and gambling disorder, with epigenetic DNA methylation and histone post-translational negative methylation identified as discussed in this article. There are 70 articles listed in PUBMED for DNA methylation and 20 articles listed for histone methylation as of October 19, 2022. For this commentary, we did not denote DNA and/or histone methylation; instead, we provided a brief summary based on behavioral effects. Based on the fact that Blum and Noble characterized the DRD2 Taq A1 allele as a generalized reward gene and not necessarily specific alcoholism, it now behooves the field to find ways to either use effector moieties to edit the neuroepigenetic insults or possibly harness the idea of potentially removing negative mRNA-reduced expression by inducing "dopamine homeostasis."
The introduction of quinoa into new growing regions and environments is of interest to farmers, consumers, and stakeholders around the world. Many plant breeding programs have already started to adapt quinoa to the environmental and agronomic conditions of their local fields. Formal quinoa breeding efforts in Washington State started in 2010, led by Professor Kevin Murphy out of Washington State University. Preharvest sprouting appeared as the primary obstacle to increased production in the coastal regions of the Pacific Northwest. Preharvest sprouting (PHS) is the undesirable sprouting of seeds that occurs before harvest, is triggered by rain or humid conditions, and is responsible for yield losses and lower nutrition in cereal grains. PHS has been extensively studied in wheat, barley, and rice, but there are limited reports for quinoa, partly because it has only recently emerged as a problem. This study aimed to better understand PHS in quinoa by adapting a PHS screening method commonly used in cereals. This involved carrying out panicle-wetting tests and developing a scoring scale specific for panicles to quantify sprouting. Assessment of the trait was performed in a diversity panel (N = 336), and the resulting phenotypes were used to create PHS tolerance rankings and undertake a GWAS analysis (n = 279). Our findings indicate that PHS occurred at varying degrees across a subset of the quinoa germplasm tested and that it is possible to access PHS tolerance from natural sources. Ultimately, these genotypes can be used as parental lines in future breeding programs aiming to incorporate tolerance to PHS.
BACKGROUND: Complex models combining impairment-based control assessments with clinical characteristics and biomarkers have been developed to predict asthma exacerbations. The composite Asthma Impairment and Risk Questionnaire (AIRQ) with adjustments for demographics (age, sex, race, and body mass index) predicts 12-month exacerbation occurrence similarly to these more complex models. OBJECTIVE: To examine whether AIRQ exacerbation prediction is enhanced when models are adjusted for a wider range of clinical characteristics and biomarkers. METHODS: Patients aged 12 years and older completed monthly online surveys regarding exacerbation-related oral corticosteroid use, emergency department or urgent care visits, and hospitalizations. Univariate logistic regressions to predict exacerbations were performed with sociodemographics, comorbidities, exacerbation history, lung function, blood eosinophils, IgE, and FeNO. Significant (P ≤ .05) variables were included in multivariable logistic regressions with and without AIRQ control categories to predict 12-month exacerbations (log odds ratio [95% Wald confidence interval]). Model performances were compared. RESULTS: Over 12 months, 1,070 patients (70% female; mean [SD] age, 43.9 [19.4] years; 22% non-White; body mass index [SD], 30.6 [8.7]) completed one or more survey (mean [SD], 10.5 [2.8] surveys). In the multivariable analysis, AIRQ control category adjusted for significant clinical characteristics and biomarkers was predictive of one or more exacerbations: odds ratio (95% CI) not well-controlled versus well-controlled: 1.93 (1.41-2.62), very poorly controlled versus well-controlled: 3.81 (2.65-5.47). Receiver operating characteristic area under the curve (AUC) for this more complex model of exacerbation prediction (AUC = 0.72) did not differ from AIRQ (AUC = 0.70). Models with AIRQ performed better than those without AIRQ (AUC = 0.67; P < .05). CONCLUSION: Costly and time-consuming complex modeling with clinical characteristics and biomarkers does not enhance the strong exacerbation prediction ability of AIRQ.
BACKGROUND: Medicines reviews by general practice pharmacists improve patient outcomes, but little is known about the associated economic outcomes, particularly in patients at higher risk of medicines-related harm. AIM: To conduct an economic cost-benefit analysis of pharmacists providing person-centred medicines reviews to patients with hyperpolypharmacy (prescribed ≥ 10 regular medicines) and/or at high risk of medicines-related harm across multiple general practice settings. METHOD: Service delivery costs were calculated based on the pharmacist's salary, recorded timings, and a general practitioner fee. Direct cost savings were calculated from the cost change of patients' medicines post review, projected over 1 year. Indirect savings were calculated using two models, a population-based model for avoidance of hospital admissions due to adverse drug reactions and an intervention-based model applying a probability of adverse drug reaction avoidance. Sensitivity analyses were performed using varying workday scenarios. RESULTS: Based on 1471 patients (88.4% with hyperpolypharmacy), the cost of service delivery was 153 per review. Using the population-based model, net cost savings ranging from 198 to 288 per patient review and from 73,317 to 177,696 per annum per pharmacist were calculated. Using the intervention-based model, net cost savings of 651-741 per review, with corresponding annual savings of 240,870-457,197 per annum per pharmacist, were calculated. Savings ratios ranged from 181 to 584% across all models and inputs. CONCLUSION: Person-centred medicines reviews by general practice pharmacists for patients at high risk of medicines-related harm result in substantial cost savings. Wider investment in general practice pharmacists will be beneficial to minimise both patient harm and healthcare system expenditure.
BACKGROUND: National and international asthma guidelines and reports do not include control tools that combine impairment assessment with exacerbation history in one instrument. OBJECTIVE: To analyze the performance of the composite Asthma Impairment and Risk Questionnaire (AIRQ) in assessing both domains of control and predicting exacerbation risk compared with the Global Initiative for Asthma (GINA) 4-question symptom control tool (GINA SCT), Asthma Control Test (ACT), and physician expert opinion (EO) informed by GINA SCT responses and appraisal of GINA-identified risk factors for poor asthma outcomes. METHODS: Multivariable logistic regressions evaluated AIRQ and GINA SCT as predictors of ACT. McNemar's test compared the proportion of patients categorized at baseline as completely or well-controlled by each assessment but with current impairment or previous-year and subsequent-year exacerbations. RESULTS: The analysis included 1064 patients aged 12 years or older; mean (SD) age 43.8 years (19.3); 70% female; 79% White; and 6% Hispanic or Latino. AIRQ and GINA SCT were highly predictive of ACT well-controlled vs not well-controlled and very poorly controlled (receiver operator characteristic area under curve AIRQ = 0.90, GINA SCT = 0.86, P = .03 AIRQ vs GINA SCT) and ACT very poorly controlled vs well-controlled and not well-controlled asthma (receiver operator characteristic area under curve AIRQ = 0.91, GINA SCT = 0.87, P = .01 AIRQ vs GINA SCT). AIRQ rated fewer patients as having completely or well-controlled asthma who had current impairment (P < .01) or with previous-year and subsequent-year exacerbations (P < .001) than did GINA SCT, ACT, and EO. CONCLUSION: AIRQ performs better in assessing both domains of current control and predicting exacerbation risk than do control tools and EO informed by GINA SCT and risk factors for poor asthma outcomes.
INTRODUCTION: Clinical reasoning skills are essential for decision-making. Current assessment methods are limited when testing clinical reasoning and management of uncertainty. This study evaluates the reliability, validity and acceptability of Practicum Script, an online simulation-based programme, for developing medical students' clinical reasoning skills using real-life cases. METHODS: In 2020, we conducted an international, multicentre pilot study using 20 clinical cases with 2457 final-year medical students from 21 schools worldwide. Psychometric analysis was performed (n = 1502 students completing at least 80% of cases). Classical estimates of reliability for three test domains (hypothesis generation, hypothesis argumentation and knowledge application) were calculated using Cronbach's alpha and McDonald's omega coefficients. Validity evidence was obtained by confirmatory factor analysis (CFA) and measurement alignment (MA). Items from the knowledge application domain were analysed using cognitive diagnostic modelling (CDM). Acceptability was evaluated by an anonymous student survey. RESULTS: Reliability estimates were high with narrow confidence intervals. CFA revealed acceptable goodness-of-fit indices for the proposed three-factor model. CDM analysis demonstrated good absolute test fit and high classification accuracy estimates. Student survey responses showed high levels of acceptability. CONCLUSION: Our findings suggest that Practicum Script is a useful resource for strengthening students' clinical reasoning skills and ability to manage uncertainty.
Prevention of asthma exacerbations and reduction of systemic corticosteroid burden remain unmet needs in asthma. US asthma guidelines recommend concomitant short-acting ß2-agonist (SABA) and inhaled corticosteroid (ICS) as an alternative reliever at step 2. The Food and Drug Administration approved a pressurized metered-dose inhaler containing albuterol and budesonide for as-needed treatment or prevention of bronchoconstriction and for reducing exacerbation risk in patients with asthma aged ≥18 years. This combination is approved for use as a reliever with or without maintenance therapy, but it is not indicated for maintenance therapy (or for single maintenance and reliever therapy). Intervening with as-needed SABA-ICS during the window of opportunity to reduce inflammation during loss of asthma control can reduce exacerbation risk, by exerting both genomic and nongenomic anti-inflammatory effects. We propose that the use of albuterol-budesonide rather than albuterol as a reliever to manage episodic symptoms driven by acute bronchoconstriction and airway inflammation can improve outcomes. This combination approach, shown to decrease asthma exacerbations and oral corticosteroid burden in patients with moderate-to-severe asthma, represents a paradigm shift for asthma treatment in the United States. Further safety and efficacy studies should provide evidence that this type of reliever should be standard of care.
Anti-Asthmatic Agents , Asthma , Humans , Adolescent , Adult , Budesonide/therapeutic use , Albuterol/therapeutic use , Ethanolamines/adverse effects , Asthma/drug therapy , Asthma/chemically induced , Adrenal Cortex Hormones , Administration, Inhalation , Inflammation/drug therapy , Formoterol Fumarate/therapeutic use , Bronchodilator Agents/therapeutic use
Background: Severe, uncontrolled asthma and asthma exacerbations in children are associated with abnormal lung function and airway development, and increased risk of chronic obstructive lung disease in adulthood. The rationale for this post hoc analysis was to explore the relationship between changes in asthma exacerbation rates and lung function in children treated with dupilumab. Methods: This post hoc analysis included children aged 6 to 11 years with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide ≥20 ppb) who received dupilumab or placebo in the phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959). Endpoints were the proportion of patients achieving clinically meaningful improvements (≥5% or ≥10%) in pre-bronchodilator percent-predicted forced expiratory volume in 1 second (ppFEV1) by Week 12, annualized severe asthma exacerbation rates from Week 12-52, and mean change from baseline in ppFEV1 to Week 12. Results: At Week 12 of VOYAGE, 141/236 (60%) of children treated with dupilumab and 57/114 (50%) of children receiving placebo showed improvements of ≥5% in ppFEV1; 106/236 (45%) children receiving dupilumab and 36/114 (32%) receiving placebo achieved improvements in ppFEV1 ≥10%. During the Week 12-52 treatment period, dupilumab vs placebo significantly reduced severe exacerbation rates in all subgroups by 52-60% (all P<0.05). Dupilumab treatment resulted in rapid and sustained improvements in ppFEV1 (Week 12 least squares mean difference [95% CI] vs placebo: 3.54 [0.30, 6.78] percentage points; P=0.03) in children who achieved improvements of ≥5%. Conclusion: Dupilumab vs placebo significantly improved pre-bronchodilator ppFEV1, with a higher proportion of patients achieving a clinically meaningful response at Week 12. Dupilumab also significantly reduced severe exacerbation rates, independent of pre-bronchodilator ppFEV1 response at Week 12. Trial Registration: NCT02948959.
BACKGROUND: The Asthma Impairment and Risk Questionnaire (AIRQ) is a 10-item, yes/no, equally weighted control tool. Lower scores indicate better control. Moreover, 7 impairment items reflect previous 2-week symptoms, and 3 risk items assess previous 12-month exacerbations. The Follow-up AIRQ for use between annual assessments has a 3-month recall period for exacerbation items. OBJECTIVE: To evaluate the responsiveness of the AIRQ over time and identify a minimal important difference (MID). METHODS: The AIRQ longitudinal study data were analyzed from patients with asthma aged 12 years and older. Anchor-based methods assessed differences in AIRQ scores relative to Patient Global Impression of Change, the accepted MIDs for St. George's Respiratory Questionnaire and Asthma Control Test, and exacerbation occurrence over 12 months. Baseline and 12-month data reflected 12-month recall AIRQ scores; Follow-up AIRQ scores were used for 3-, 6-, and 9-month analyses. RESULTS: A total of 1070 patients were included. The Patient Global Impression of Change rating of "much improved" was associated with AIRQ mean score changes from baseline to months 3, 6, 9, and 12 of -2.0, -1.9, -1.9, and -1.8, respectively. The mean AIRQ score change among patients who met the St. George's Respiratory Questionnaire MID (≥4-point decrease) was -1.8 at 6 and 12 months. The AIRQ mean scores decreased from baseline by -2.2 to -2.5 points at months 3, 6, 9, and 12 for patients who met the Asthma Control Test MID (≥ 3-point increase). A 2-point higher baseline AIRQ score was associated with a 1.7 odds ratio of 12-month exacerbation occurrence (95% CI, 1.53-1.89). CONCLUSION: A change score of 2 is recommended as the AIRQ MID.
Peptide YY (PYY3-36) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY3-36 preferring receptor (neuropeptide Y (NPY) Y2 receptor (Y2R)) in the afferent vagus nerve is required for the appetite inhibitory effects of physiologically-released PYY3-36, but not peripherally administered pharmacological doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is not evident in the germline model. Loss of vagal Y2R signalling also results in altered meal patterning associated with accelerated gastric emptying. These results are important for the design of PYY-based anti-obesity agents.
Gastrointestinal Hormones , Peptide YY , Peptide YY/physiology , Appetite/physiology , Vagus Nerve , Eating
BOLD fMRI signal has been used in conjunction with vasodilatory stimulation as a marker of cerebrovascular reactivity (CVR): the relative change in cerebral blood flow (CBF) arising from a unit change in the vasodilatory stimulus. Using numerical simulations, we demonstrate that the variability in the relative BOLD signal change induced by vasodilation is strongly influenced by the variability in deoxyhemoglobin-containing cerebral blood volume (CBV), as this source of variability is likely to be more prominent than that of CVR. It may, therefore, be more appropriate to describe the relative BOLD signal change induced by an isometabolic vasodilation as a proxy of deoxygenated CBV (CBVdHb) rather than CVR. With this in mind, a new method was implemented to map a marker of CBVdHb, termed BOLD-CBV, based on the normalization of voxel-wise BOLD signal variation by an estimate of the intravascular venous BOLD signal from voxels filled with venous blood. The intravascular venous BOLD signal variation, recorded during repeated breath-holding, was extracted from the superior sagittal sinus in a cohort of 27 healthy volunteers and used as a regressor across the whole brain, yielding maps of BOLD-CBV. In the same cohort, we demonstrated the potential use of BOLD-CBV for the normalization of stimulus-evoked BOLD fMRI by comparing group-level BOLD fMRI responses to a visuomotor learning task with and without the inclusion of voxel-wise vascular covariates of BOLD-CBV and the BOLD signal change per mmHg variation in end-tidal carbon dioxide (BOLD-CVR). The empirical measure of BOLD-CBV accounted for more between-subject variability in the motor task-induced BOLD responses than BOLD-CVR estimated from end-tidal carbon dioxide recordings. The new method can potentially increase the power of group fMRI studies by including a measure of vascular characteristics and has the strong practical advantage of not requiring experimental measurement of end-tidal carbon dioxide, unlike traditional methods to estimate BOLD-CVR. It also more closely represents a specific physiological characteristic of brain vasculature than BOLD-CVR, namely blood volume.
Carbon Dioxide , Magnetic Resonance Imaging , Humans , Magnetic Resonance Imaging/methods , Cerebral Blood Volume , Brain/physiology , Brain Mapping/methods , Cerebrovascular Circulation/physiology , Oxygen
OBJECTIVES: The use of parenteral systemic anticancer therapy (SACT) has led to improved cancer survival. A quality assurance (QA) system of the aseptic compounding process is necessary to ensure safe and consistent production of parenteral SACT. This scoping review identifies international evidence and practice relating to QA standards in the preparation of parenteral SACT in healthcare establishments. METHODS: Standards relating to aseptic compounding in hospital pharmacies and literature exploring the aseptic compounding of parenteral SACT were included. Literature relating to the non-aseptic compounding of medicines and records specific to sterile manufacturing in industrial settings were excluded. A search of several electronic databases, trial registries, the grey literature and websites of key European hospital pharmacy groups and accreditation bodies was conducted on 16 March 2022. A narrative discussion was performed by country, and content analysis of articles was conducted. RESULTS: Thirty-seven records were included. Standards reviewed covered the work environment, the preparation process and the safety of the workers who are potentially exposed to hazardous chemicals. It was a common practice to include frequent audits to ensure adherence to standards. Some standards also recommended external inspections to allow for further learnings. Periodic reviews are encouraged to ensure standards maintain relevance. National standards of the countries reviewed were based on international standards, with minor adaptations for local conditions. CONCLUSIONS: The main limitation of this review is that it is limited to countries with a high human development index. The review shows that the use of an internationally recognised standard as a basis for national standards is best practice, and will allow for relevance into the future.
Parenteral Nutrition , Pharmacy Service, Hospital , Humans , Drug Compounding , Delivery of Health Care
Gender-affirming hormone replacement therapy (gaHRT) is an important step for many in the gender diverse community, associated with increased quality-of-life and lower self-reported scores of depression and anxiety. However, considering the interactions that the involved sex hormones have on vasculature (with oestrogen and testosterone demonstrating vasodilatory and vasoconstricting properties, respectively), it is important for transgender healthcare research to examine how the manipulation of these hormones interact with cerebrovascular structure and functioning. There is a stark lack of research in this area. This mini-review outlines the research suggesting a vascular impact of these sex hormones using evidence from a range of cohorts (e.g., menopause, polycystic ovary syndrome) and discusses the work that has been done into cerebrovascular changes following gaHRT. Finally, recommendations for future research into cerebrovascular health in transgender cohorts following gaHRT are outlined.
BACKGROUND: Genome-wide association studies demonstrate that Alzheimer's disease (AD) has a highly polygenic architecture, where thousands of independent genetic variants explain risk with high classification accuracy. This AD polygenic risk score (AD-PRS) has been previously linked to preclinical cognitive and neuroimaging features observed in asymptomatic individuals. However, shared variance between AD-PRS and neurocognitive features are small, suggesting limited preclinical utility. METHODS: Here, we recruited sixteen clinically asymptomatic individuals (mean age 67; range 58-76) with either extremely low / high AD-PRS (defined as at least 2 standard deviations from the wider sample mean (N = 4504; N EFFECTIVE = 90)) with comparable age sex and education level. We assessed group differences in autobiographical memory and T1-weighted structural neuroimaging features. RESULTS: We observed marked reductions in autobiographical recollection (Cohen's d = - 1.66; P FDR = 0.014) and midline structure (cingulate) thickness (Cohen's d = - 1.55, P FDR = 0.05), with no difference in hippocampal volume (P > 0.3). We further confirm the negative association between AD-PRS and cingulate thickness in a larger study with a comparable age (N = 31,966, ß = - 0.002, P = 0.011), supporting the validity of our approach. CONCLUSIONS: These observations conform with multiple streams of prior evidence suggesting alterations in cingulate structures may occur in individuals with higher AD genetic risk. We were able to use a genetically informed research design strategy that significantly improved the efficiency and power of the study. Thus, we further demonstrate that the recall-by-genotype of AD-PRS from wider samples is a promising approach for the detection, assessment, and intervention in specific individuals with increased AD genetic risk.
Alzheimer Disease , Humans , Aged , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Gyrus Cinguli/diagnostic imaging , Genome-Wide Association Study , Genotype , Neuroimaging
Loneliness, an established risk factor for both, mental and physical morbidity, is a mounting public health concern. However, the neurobiological mechanisms underlying loneliness-related morbidity are not yet well defined. Here we examined the role of genes and associated DNA risk polymorphic variants that are implicated in loneliness via genetic and epigenetic mechanisms and may thus point to specific therapeutic targets. Searches were conducted on PubMed, Medline, and EMBASE databases using specific Medical Subject Headings terms such as loneliness and genes, neuro- and epigenetics, addiction, affective disorders, alcohol, anti-reward, anxiety, depression, dopamine, cancer, cardiovascular, cognitive, hypodopaminergia, medical, motivation, (neuro)psychopathology, social isolation, and reward deficiency. The narrative literature review yielded recursive collections of scientific and clinical evidence, which were subsequently condensed and summarized in the following key areas: (1) Genetic Antecedents: Exploration of multiple genes mediating reward, stress, immunity and other important vital functions; (2) Genes and Mental Health: Examination of genes linked to personality traits and mental illnesses providing insights into the intricate network of interaction converging on the experience of loneliness; (3) Epigenetic Effects: Inquiry into instances of loneliness and social isolation that are driven by epigenetic methylations associated with negative childhood experiences; and (4) Neural Correlates: Analysis of loneliness-related affective states and cognitions with a focus on hypodopaminergic reward deficiency arising in the context of early life stress, eg, maternal separation, underscoring the importance of parental support early in life. Identification of the individual contributions by various (epi)genetic factors presents opportunities for the creation of innovative preventive, diagnostic, and therapeutic approaches for individuals who cope with persistent feelings of loneliness. The clinical facets and therapeutic prospects associated with the current understanding of loneliness, are discussed emphasizing the relevance of genes and DNA risk polymorphic variants in the context of loneliness-related morbidity.
Introduction: Quinoa is a high-value, nutritious crop that performs well in variable environments, marginal soils, and in diverse crop rotations. Quinoa's many attributes make it an ideal crop for supporting human health in global communities and economies. To date, quinoa research has largely focused on traits in adult plants important for enhancing plant phenotypic plasticity, abiotic stress, disease resistance, and yield. Fewer studies have evaluated quinoa seed dormancy and suggest that most modern quinoa varieties have weak or no seed dormancy, and a narrow window of seed viability post-harvest. In other crops, diminished seed dormancy is a major risk factor for preharvest sprouting (PHS; germination on the panicle due to rain prior to harvest) and may also pose a similar risk for quinoa. Methods: This study (1) developed a dormancy screening assay to characterize seed dormancy strength in a large collection of quinoa varieties, (2) investigated if morphological variables including seed coat color, seed coat thickness, seed shape including eccentricity which evaluates the roundness or flatness of a seed, and other agronomic traits like crude protein content and seed moisture, contribute to quinoa seed dormancy, and (3) evaluated the use of a phenetic modeling approach to explore relationships between seed morphology and seed dormancy. Results: Dormancy screening indicated seed dormancy ranges in quinoa varieties from none to strong dormancy. Further, phenetic modeling approaches indicate that seed coat thickness and eccentricity are important morphological variables that impact quinoa seed dormancy strength. Conclusions: While dormancy screening and phenetic modeling approaches do not provide a direct solution to preventing PHS in quinoa, they do provide new tools for identifying dormant varieties as well as morphological variables contributing to seed dormancy.
