Maternal plasma cortisol's effect on offspring birth weight: a Mendelian Randomisation study.

BACKGROUND: Observational studies and randomized controlled trials have found evidence that higher maternal circulating cortisol levels in pregnancy are associated with lower offspring birth weight. However, it is possible that the observational associations are due to residual confounding. METHODS: We performed two-sample Mendelian Randomisation (MR) using a single genetic variant (rs9989237) associated with morning plasma cortisol (GWAS; sample 1; N = 25,314). The association between this maternal genetic variant and offspring birth weight, adjusted for fetal genotype, was obtained from the published EGG Consortium and UK Biobank meta-analysis (GWAS; sample 2; N = up to 406,063) and a Wald ratio was used to estimate the causal effect. We also performed an alternative analysis using all GWAS reported cortisol variants that takes account of linkage disequilibrium. We also tested the genetic variant's effect on pregnancy cortisol and performed PheWas to search for potential pleiotropic effects. RESULTS: The estimated effect of maternal circulating cortisol on birth weight was a 50 gram (95% CI, -109 to 10) lower birth weight per 1 SD higher log-transformed maternal circulating cortisol levels, using a single variant. The alternative analysis gave similar results (-33 grams (95% CI, -77 to 11)). The effect of the cortisol variant on pregnancy cortisol was 2-fold weaker than in the original GWAS, and evidence was found of pleiotropy. CONCLUSIONS: Our findings provide some evidence that higher maternal morning plasma cortisol causes lower birth weight. Identification of more independent genetic instruments for morning plasma cortisol are necessary to explore the potential bias identified.

Mind the NIH-Funding Gap: Structural Discrimination in Physical Health-Related Research for Cognitively Able Autistic Adults.

Autistic adults experience disparities in physical health and health care access. A major barrier to addressing these disparities is a lack of federal funding for research on this topic. In seeking funding from the National Institutes of Health (NIH), we discovered nodes that contribute to structural discrimination in physical health-related research for autistic adults. To examine this structural discrimination, we systematically searched funded research on all physical health-disparity conditions in autistic adults using NIH RePORTER. Among 61 unique studies, none focused on improving the relevant physical health condition through intervention, programs, or services for autistic adults. Thus, we need updated policies and procedures that support research on physical health disparities in populations with developmental or mental health conditions.

Appropriateness, Acceptability, and Feasibility of a Neurodiversity-Based Self-determination Program for Autistic Adults.

Published self-determination programs do not adequately address the needs of autistic adults. We designed a multi-component self-determination program, grounded in the neurodiversity paradigm, to help autistic adults achieve goals to improve their quality of life. The first phase involved 5 days of psychoeducation, practice, and social events; the second phase included 3 months of telecoaching; and the third phase included follow-up. Thirty-four university students coached 31 autistic adults on three evolving goals. On average, participants completed one goal per week. Most participants were satisfied with the program. We found that the program was appropriate, acceptable, and feasible. This program is a promising approach to helping autistic adults gain self-determination skills and improve their quality of life.

Peer-led exercise program for ageing adults to improve physical functions - a randomized trial.

BACKGROUND: A peer-led exercise program is one way to empower people sharing similar characteristics to encourage others to be active, but there is a lack of evidence that these programs have physical function and other benefits when delivered to ageing adults. METHODS: This randomized controlled trial lasting 12 weeks proposed an exercise peer-led program offered to 31 adults aged 50 and above, twice a week, by a trained leader of the same age from March to May 2019. The program was offered for free with limited space and equipment. Valid tests of physical function (e.g., 30-s chair stand, 6-min walk test) were used to assess the functional benefits. Psychosocial outcomes were assessed using self-reported questionnaires and metabolic outcomes via a fasted blood draw. RESULTS: A significant difference was found between pre-and post-values in most physical function tests in the intervention group (all p < 0.05). When adjusted for potential confounders, the intervention group was significantly associated with a more significant improvement on the chair stand test (ß = .26; p < 0.001; r2 = 0.26), the arm curl (ß = .29; p < 0.001; r2 = 0.49), as well as the 6-min walk test (ß = -.14; p < 0.001; r2 = 0.62) compared with the control group. Using repetitive measures generalized linear model, the interaction between the changes and the group was significant for all three tests. Benefits were also observed for participants' stress level and perceived health in the intervention group compared to the control. Finally, no significant difference was observed between groups for metabolic health. CONCLUSIONS: The current work suggests that a 12-week peer-led exercise program can improve physical function for adults age 50 and above. TRIAL REGISTRATION: NCT03799952 (ClinicalTrials.gov) 12/20/2018.

The broader autism phenotype constellations-disability matrix paradigm: Theoretical model for autism and the broader autism phenotype.

The prevalence of autism has increased dramatically over the last 60 years, and the cause of this increase is unclear. In this paradigm-shift paper, I propose an explanatory paradigm for the cause of autism and its increased prevalence in the general population. I also discuss how social and historical contexts may have influenced the evolution and manifestation of specific traits in the autism population. These traits expand the characterization of the broader autism phenotype to include a constellation of socially valued traits, termed Broader Autism Phenotype Constellations (BAPCO). The frequency of these traits may have increased due to assortative mating opportunities that occurred alongside social changes in education and occupational opportunities over the last 100 years. I propose that assortative mating can lead to both positive and negative developmental consequences affecting social and language development. I also propose that BAPCO traits, which are not intrinsically disabilities, could interact with co-occurring conditions in a new model called the BAPCO-Disability Matrix Paradigm (BAPCO-DMAP). In this paradigm, autism is located at the intersection of BAPCO traits and at least one co-occurring condition. These proposed models support the need to create a more comprehensive definition of autism that includes constellations of BAPCO traits. The BAPCO-DMAP paves the way to testable predictions of autism prevalence and provides a framework to better understand the foundational traits of autism. Finally, this paradigm radically redefines the broader autism phenotype with characteristics that can inform therapy and child development.

Clinical profiles of post-load glucose subgroups and their association with glycaemic traits over time: An IMI-DIRECT study.

AIM: To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. METHODS: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. RESULTS: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1-4. Participants in Subgroups 2-4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (ß = 0.36, 95% CI 0.13-0.58), Subgroup 3 (ß = 0.30; 95% CI 0.10-0.50) and Subgroup 2 (ß = 0.18; 95% CI 0.04-0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. CONCLUSIONS: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.

Quo Vadis? A question of historical awareness.

AIM: To emphasize the role of history in shaping clinical nursing identity and opportunities, and encourage nurses' contribution to the story of contemporary clinical nursing. APPROACH: Drawing upon history frameworks and approaches to history research, greater engagement of clinical nurses in recording nursing history is canvassed. A basic framework for developing historical research from practice narratives is suggested as a feasible option. OUTCOMES: Topics identified: a) nurses' awareness of their history and nursing's professional standing; b) the importance of oral history in nursing development; and c) digital influences on history research and constructing historical narratives. CONCLUSION: Clinical nurses' stories contribute to historical research. All nurses are responsible for gathering and distributing contemporary local narratives on clinical nursing. Oral history research provides a framework for nurses to record and share stories. IMPLICATIONS: Recorded history can prevent nursing from being trivialized or misrepresented. Missing accounts of contemporary nursing create gaps in our narrative and risk future professional disempowerment.

Autism Identity and the "Lost Generation": Structural Validation of the Autism Spectrum Identity Scale (ASIS) and Comparison of Diagnosed and Self-Diagnosed Adults on the Autism Spectrum.

BACKGROUND: A population segment of autistic adults are under-identified due, in part, to historic changes in criteria for diagnosing autism and diagnostic biases related to gender, socioeconomic status, and other individual characteristics such as intellectual functioning. Some of these individuals, described as the "lost generation", may choose to self-diagnose. Although little is known about this population, it is possible that they share similar self-conceptualizations or internalized stigma as their diagnosed counterparts. This study reports on the structural validity of the Autism Spectrum Identity Scale (ASIS) with individuals diagnosed and self-diagnosed with autism and compares the demographic characteristics, stigma, self-concept, and quality of life of these two groups. METHODS: Over 1000 adults diagnosed (n = 893) or self-diagnosed (n = 245) with autism were recruited through organizations serving the autism community to participate in a nationally distributed online survey that included demographic questions and measures for stigma, self-concept, quality of life, and wellbeing. The diagnosed dataset was randomly split with exploratory factor analysis performed on a training dataset. Split-half cross-validation was used to predict the factor structure of the holdout dataset. Then, the full diagnosed dataset structure was used to determine the generalizability of the factor structure to the self-diagnosed dataset. The diagnosed and self-diagnosed were also compared for differences in gender, age, employment status, diagnostic term preference, and factors of self-concept (autism identity and self-esteem), stigma, and quality of life. RESULTS: Factor analysis of diagnosed participants yielded a four-factor structure, consistent with previous research, with strong split-sample cross-validation and good internal consistency. Factor predictions of the self-diagnosed dataset from the diagnosed dataset ranged from .97 - 1.00 with similar internal consistency. Self-diagnosed participants were more likely to be older, women, or employed and less likely to be students or prefer the term "autism" than those with an autism diagnosis. The groups were remarkably similar in reported stigma, self-esteem, quality of life and in ASIS factors; both groups reported lower quality of life than the general population. CONCLUSIONS: The ASIS demonstrated the same internal structure with both the diagnosed and self-diagnosed. The profile of self-diagnosed participants matches the profile hypothesized for the "lost generation" and others at risk of being under-identified for autism. Both populations appear to be similarly struggling with employment, stigma, and quality of life. Future research should examine whether self-diagnosed individuals meet criteria for autism or could benefit from interventions, programs, or services serving autism communities.

Correction to: Discriminative and Criterion Validity of the Autism Spectrum Identity Scale (ASIS).

The original version of this article contains an error in Results and Discussion sections and in Table 2. The corrected text and table are given below. Results:  Participants' scores were higher for overall stigma and discrimination than those reported by King et al (2007). The pattern of descriptive statistics for the AAQOL was simialr to that reported by Brod et al. (2006). Discussion: Of note, participants in this study scored approximately 30 points lower than the non-ADHD scores on the AAQOL as reported by Brod and colleagues (2006). The distribution of scores in the current study more closely resembled the distribution of scores by those with ADHD than the non-ADHD control group. This is consistent with the widespread reports of decreased quality of life for adults on the autism spectrum (e.g., Howlin and Moss 2012; Taylor & Seltzer 2011). Further, and consistent with reports of increased stigma (e.g., Shtayermnan, 2009; Tyman, Salor, Saia, et al. 2010), participants in this study scored approximately 20 points higher for overall stigma, and ten points higher for discrimination, than participants with mental illness as reported by King and colleagues (2007).

Type 1 diabetes genetic risk score discriminates between monogenic and Type 1 diabetes in children diagnosed at the age of <5 years in the Iranian population.

AIM: To examine the extent to which discriminatory testing using antibodies and Type 1 diabetes genetic risk score, validated in European populations, is applicable in a non-European population. METHODS: We recruited 127 unrelated children with diabetes diagnosed between 9 months and 5 years from two centres in Iran. All children underwent targeted next-generation sequencing of 35 monogenic diabetes genes. We measured three islet autoantibodies (islet antigen 2, glutamic acid decarboxylase and zinc transporter 8) and generated a Type 1 diabetes genetic risk score in all children. RESULTS: We identified six children with monogenic diabetes, including four novel mutations: homozygous mutations in WFS1 (n=3), SLC19A2 and SLC29A3, and a heterozygous mutation in GCK. All clinical features were similar in children with monogenic diabetes (n=6) and in the rest of the cohort (n=121). The Type 1 diabetes genetic risk score discriminated children with monogenic from Type 1 diabetes [area under the receiver-operating characteristic curve 0.90 (95% CI 0.83-0.97)]. All children with monogenic diabetes were autoantibody-negative. In children with no mutation, 59 were positive to glutamic acid decarboxylase, 39 to islet antigen 2 and 31 to zinc transporter 8. Measuring zinc transporter 8 increased the number of autoantibody-positive individuals by eight. CONCLUSIONS: The present study provides the first evidence that Type 1 diabetes genetic risk score can be used to distinguish monogenic from Type 1 diabetes in an Iranian population with a large number of consanguineous unions. This test can be used to identify children with a higher probability of having monogenic diabetes who could then undergo genetic testing. Identification of these individuals would reduce the cost of treatment and improve the management of their clinical course.

Persistent C-peptide is associated with reduced hypoglycaemia but not HbA1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?

AIMS: Most people with Type 1 diabetes have low levels of persistent endogenous insulin production. The Diabetes Control and Complications Trial showed that close to diagnosis preserved endogenous insulin was associated with lower HbA1c , hypoglycaemia and complication rates, when intensively treated. We aimed to assess the clinical impact of persistent C-peptide on rate of hypoglycaemia and HbA1c in those with long duration (> 5 years) Type 1 diabetes. METHODS: We conducted a cross-sectional case-control study of 221 people (median age 24 years) with Type 1 diabetes. We confirmed ongoing endogenous insulin secretion by measuring C-peptide after a mixed-meal tolerance test. We compared self-reported hypoglycaemia (n = 160), HbA1c , insulin dose and microvascular complications (n = 140) in those with preserved and low C-peptide. RESULTS: Stimulated median (IQR) C-peptide was 114 (43, 273) pmol/l and < 3 (< 3, < 3) pmol/l in those with preserved and low C-peptide respectively. Participants with preserved C-peptide had lower reported monthly rates of hypoglycaemia, with 21% fewer symptomatic episodes, 5.9 vs. 7.5 [incidence rate ratio (IRR) 0.79, P = 0.001], and 65% fewer asymptomatic episodes, 1.0 vs. 2.9 (IRR 0.35, P < 0.001). Those with preserved C-peptide had a lower insulin dose (0.68 vs. 0.81 units/kg, P = 0.01) but similar HbA1c (preserved 69 vs. low 67 mmol/mol, P = 0.06). CONCLUSIONS: Adults with Type 1 diabetes and preserved endogenous insulin production receiving usual care in the UK have lower daily insulin doses and fewer self-reported hypoglycaemic episodes, but no difference in HbA1c . This is consistent with non-intensive treatment in previous studies, and suggests a need to consider therapy intensification to gain full benefit of preserved endogenous insulin.

Correction to: Trend estimation for complex survey designs of water chemistry indicators from Sierra Nevada Lakes.

The original version of this article contained a misaligned equation. The following equation replaces the online printed on the 5th page of the article.

Trend estimation for complex survey designs of water chemistry indicators from Sierra Nevada Lakes.

Surveys for long-term monitoring programs managing natural resources often incorporate sampling design complexity. However, design weights are often ignored in trend models of data from complex sampling designs. Generalized random tessellation stratified samples of a simulated population of lakes are selected with various levels of survey design complexity, and three trend approaches are compared. We compare an unweighted trend model, linear regression models of the trend in design-based estimates of annual status, and a probability-weighted iterative generalized least squares (PWIGLS) approach with a linearization variance. The bias and confidence interval coverage of the trend estimate and the size and power of the trend test are used to evaluate weighted and unweighted approaches. We find that the unweighted approach often outperforms the other trend approaches by providing high power for trend detection and nominal confidence interval coverage of the true trend regression parameter. We also find that variance composition and revisit design structure affect the performance of the PWIGLS estimator. When a subpopulation exhibiting an extreme trend is sampled disproportionately to its occurrence in the population, the unweighted approach may produce biased estimates of trend with poor confidence interval coverage. We recommend considering variance composition and potential subpopulation trends when selecting sampling designs and trend analysis approaches.

Faecal calprotectin effectively excludes inflammatory bowel disease in 789 symptomatic young adults with/without alarm symptoms: a prospective UK primary care cohort study.

BACKGROUND: Primary care faecal calprotectin testing distinguishes inflammatory bowel disease (IBD) from functional gut disorder in young patients presenting with abdominal symptoms; however, previous evaluations have excluded patients with alarm symptoms. AIMS: We sought to evaluate the diagnostic accuracy of calprotectin to distinguish IBD from functional gut disorder in young adults in whom general practitioners (GPs) suspected IBD; including patients reporting gastrointestinal alarm symptoms. We hypothesised that calprotectin would reduce secondary care referrals and healthcare costs. METHODS: We undertook a prospective cohort study of 789 young adults (18-46 years old) presenting with gastrointestinal symptoms to 49 local general practices that had undergone calprotectin testing (1053 tests: between Jan 2014 and May 2016) because of suspected IBD. We considered calprotectin levels of ≥100 µg/g positive. Primary and secondary care records over 12 months from the point of calprotectin testing were used as the reference standard. RESULTS: Overall, 39% (308/789) patients reported gastrointestinal alarm symptoms and 6% (50/789) tested patients were diagnosed with IBD. The positive and negative predictive values of calprotectin testing for distinguishing IBD from functional gut disorder in patients with gastrointestinal alarm symptoms were 50% (95% CI 36%-64%) and 98% (96%-100%): and in patients without gastrointestinal alarm symptoms were 27% (16%-41%) and 99% (98%-100%), respectively. We estimate savings of 279 referrals and £160 per patient. CONCLUSIONS: Calprotectin testing of young adults with suspected IBD in primary care accurately distinguishes IBD from functional gut disorder, even in patients with gastrointestinal alarm symptoms and reduces secondary care referrals and diagnostic healthcare costs.

Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion.

Little is known about how leukemia cells alter the bone marrow (BM) niche to facilitate their own growth and evade chemotherapy. Here, we provide evidence that acute myeloid leukemia (AML) blasts remodel the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive microenvironment through exosome secretion. Either engrafted AML cells or AML-derived exosomes increased mesenchymal stromal progenitors and blocked osteolineage development and bone formation in vivo. Preconditioning with AML-derived exosomes 'primed' the animals for accelerated AML growth. Conversely, disruption of exosome secretion in AML cells through targeting Rab27a, an important regulator involved in exosome release, significantly delayed leukemia development. In BM stromal cells, AML-derived exosomes induced the expression of DKK1, a suppressor of normal hematopoiesis and osteogenesis, thereby contributing to osteoblast loss. Conversely, treatment with a DKK1 inhibitor delayed AML progression and prolonged survival in AML-engrafted mice. In addition, AML-derived exosomes induced a broad downregulation of hematopoietic stem cell-supporting factors (for example, CXCL12, KITL and IGF1) in BM stromal cells and reduced their ability to support normal hematopoiesis. Altogether, this study uncovers novel features of AML pathogenesis and unveils how AML cells create a self-strengthening leukemic niche that promotes leukemic cell proliferation and survival, while suppressing normal hematopoiesis through exosome secretion.

Discriminative and Criterion Validity of the Autism Spectrum Identity Scale (ASIS).

Individuals on the autism spectrum face stigma that can influence identity development. Previous research on the 22-item Autism Spectrum Identity Scale (ASIS) reported a four-factor structure with strong split-sample cross-validation and good internal consistency. This study reports the discriminative and criterion validity of the ASIS with other measures. Adults (n = 1139) who have, or identify with, an autism spectrum diagnosis took a nationally distributed online survey that also included demographic questions and measures for stigma, self-esteem, and quality of life (QoL). All four ASIS factors discriminated from measures of stigma and self-esteem. The ASIS also showed good criterion validity with the factors of Positive Difference and Changeability demonstrating widespread relationships with subjective quality of life in the expected directions.

Non-viral gene delivery systems: hurdles for bench-to-bedside transformation.

Biologist and Nobel Prize winner James Watson's quote, "We used to think that our fate was in our stars, but now we know that, in large measure, our fate is in our genes", represents the initial food for thought that revolutionized the way medications and active pharmaceutical ingredients are defined (Rocholl 1996). This fate engraved in the genetic material, as mentioned in Watson's quote, fueled a tremendous revolution wave in gene therapy. Gene therapy is a promising technology for treating genetic and acquired diseases by modulating the expression of a specific gene in the pathological cells. This is achieved by introducing a DNA sequence or other nucleic acid material or oligonucleotides to the target cell (Kay, 2011). Moreover, gene therapy contributes to correction of genetic defects, expression of therapeutic proteins, and inhibition of the synthesis of malignant proteins. In this review article, different non-viral gene delivery systems and their applications are discussed in detail. We reviewed and tabulated over 90 papers and 50 patents from 2006 to date discussing non-viral gene delivery technologies, innovation, and bench-to-bedside transformation. Furthermore, we are going to shed light on the lack of standardization in the design and characterization of non-viral gene delivery systems worldwide, which is a major concern in this research's field. This review would aid in getting an eagle eye view through non-viral gene delivery technologies during the past 20 years. Such a view, capturing the advances, the hurdles, and experimental details, would aid expert researchers in tuning their experimentation strategies and help newcomers better initially design their studies to generate solid and comprehensive results that can be reliable and reproducible.

Patient, family, nurse perspectives on Chinese elders' quality of life.

BACKGROUND: Families and nurses are important care-providers and proxies of older people. Their ability to assess the quality of life of elders in ways that align with how older people assess themselves has policy implications for allocating services and resources to older persons. AIM: To investigate the alignment of perspectives of the quality of life held by older people, their families and nurses in China. METHODS: Employing a survey design using concurrent EQ-5D-3L and WHOQOL-BREF surveys, responses from 72 matched stakeholder groups were compared and agreement tested using weighted kappa/one-way random intra-class correlations and paired Student's t-test. RESULTS: On the more observable dimensions families and nurses were in close agreement with the older person in relation to quality of life reports. However, in the more subjective domains, family and especially nurses tended to estimate that the older person's suffering as more severe than they themselves thought. CONCLUSION: The perspectives of older patients and their family are more closely aligned regarding the older person's quality of life than that of nurses caring for them, a finding inconsistent with international research. IMPLICATION FOR NURSING AND HEALTH POLICY: The evidence suggests that nursing work assignment processes could influence the accuracy of nurses' perceptions of their patient's quality of life.

Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.

Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.