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BackgroundPulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects delineate the PDAC syndrome. We aim to identify the cause of PDAC syndrome in patients who do not carry pathogenic variants inRARBandSTRA6, which have been previously associated with this disorder.MethodsWe sequenced the exome of patients with unexplained PDAC syndrome and performed functional validation of candidate variants.ResultsWe identified bi-allelic variants inWNT7Bin fetuses with PDAC syndrome from two unrelated families. In one family, the fetus was homozygous for the c.292C>T (p.(Arg98*)) variant whereas the fetuses from the other family were compound heterozygous for the variants c.225C>G (p.(Tyr75*)) and c.562G>A (p.(Gly188Ser)). Finally, a molecular autopsy by proxy in a consanguineous couple that lost two babies due to lung hypoplasia revealed that both parents carry the p.(Arg98*) variant. Using a WNT signalling canonical luciferase assay, we demonstrated that the identified variants are deleterious. In addition, we found thatwnt7bbmutant zebrafish display a defect of the swimbladder, an air-filled organ that is a structural homolog of the mammalian lung, suggesting that the function of WNT7B has been conserved during evolution for the development of these structures.ConclusionOur findings indicate that defective WNT7B function underlies a form of lung hypoplasia that is associated with the PDAC syndrome, and provide evidence for involvement of the WNT–β-catenin pathway in human lung, tracheal, ocular, cardiac, and renal development.

Background: The relevance of social support for weight management is not well documented in people with prediabetes. An important consideration is the adequate assessment of social provisions related to weight management in this population. Purpose: To assess the factor structure and measurement invariance of an adapted Social Provisions Scale specific to weight management (SPS-WM). Methods: Participants of a diabetes prevention trial (n=599) completed a demographic survey, and the SPS-WM. Confirmatory analyses tested the factor structure of the SPS-WM, and measurement invariance was assessed for gender, weight status, education level, and age. Results: Removal of two collinear items resulted in acceptable model fit, supporting six correlated factors for social provisions specific to weight management. Measurement invariance was supported across all subgroups. Conclusion: Results support score interpretations for these scales reflecting distinct components of social support specific to weight management in alignment with those of the original survey.

'Supplementary Table S2- Somatic mutations identified in the tumors from individuals III.6; III.7 and III.8 in family 1 and individual III.1 in family 2 among 193 DNA repair genes.'

This file includes supplementary Figure S1, Supplementary Figure S2 and Supplementary Figure S3. It also includes Supplementary Table S1 - RAD51D c.620C

'Supplementary Table3 -Presence of allelic imbalanced alleles in RAD51D and TP53 somatic mutations in RAD51D c.620C>T;p.S207L HGSC carriers.'

RAD51D is a key player in DNA repair by homologous recombination (HR), and RAD51D truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating RAD51D variants to cancer predisposition remains uncertain. Using deep sequencing and case–control genotyping studies, we show that in French Canadians, the missense RAD51D variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D–XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D–XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic RAD51D missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense RAD51D variants. Cancer Res; 77(16); 4517–29. ©2017 AACR.

Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype–phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.

Amongst the numerous genes associated with intellectual disability, SYNGAP1 stands out for its frequency and penetrance of loss-of-function variants found in patients, as well as the wide range of co-morbid disorders associated with its mutation. Most studies exploring the pathophysiological alterations caused by Syngap1 haploinsufficiency in mouse models have focused on cognitive problems and epilepsy, however whether and to what extent sensory perception and processing are altered by Syngap1 haploinsufficiency is less clear. By performing EEG recordings in awake mice, we identified specific alterations in multiple aspects of auditory and visual processing, including increased baseline gamma oscillation power, increased theta/gamma phase amplitude coupling following stimulus presentation and abnormal neural entrainment in response to different sensory modality-specific frequencies. We also report lack of habituation to repetitive auditory stimuli and abnormal deviant sound detection. Interestingly, we found that most of these alterations are present in human patients as well, thus making them strong candidates as translational biomarkers of sensory-processing alterations associated with SYNGAP1/Syngap1 haploinsufficiency.

Background Both theoretical and empirical evidence supports the potential of modest financial incentives to increase the reach of evidence-based weight control programs. However, few studies exist that examine the best incentive design for achieving the highest reach and representativeness at the lowest cost and whether or not incentive designs may be valued differentially by subgroups that experience obesity-related health disparities. Methods A discrete choice experiment was conducted (n = 1232 participants; over 90% of them were overweight/obese) to collect stated preference towards different financial incentive attributes, including reward amount, program location, reward contingency, and payment form and frequency. Mixed logit and conditional logit models were used to determine overall and subgroup preference ranking of attributes. Using the National Health and Nutrition Examination Survey data sample weights and the estimated models, we predicted US nationally representative participation rates by subgroups and examined the effect of offering more than one incentive design. External validity was checked by using a completed cluster randomized control trial. Results There were significant subgroup differences in preference toward incentive attributes. There was also a sizable negative response to larger incentive amounts among African Americans, suggesting that higher amounts would reduce participation from this population. We also find that offering participants a menu of incentive designs to choose from would increase reach more than offering higher reward amounts. Conclusions We confirmed the existence of preference heterogeneity and the importance of subgroup-targeted incentive designs in any evidence-based weight control program to maximize population reach and reduce health disparities. National Heart, Lung, and Blood Institute of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [1R21HL097308-01A2] Published version Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number 1R21HL097308-01A2. The content is solely the responsibility of the authors and does not necessarily represent the official views of the sponsoring agencies.

Background Limited research has reported the economic feasibility—from both a research and practice perspective—of efforts to recruit and enroll an intended audience in evidence-based approaches for disease prevention. This study aims to retrospectively assess and estimate the costs of a population health management (PHM) approach to identify, engage, and enroll patients in a Type 1 Hybrid Effectiveness-Implementation (HEI), diabetes-prevention trial. Methods We used descriptive analyses and activity-based costing to estimate the recruitment costs of a PHM approach integrated within a HEI trial. Measures included total costs and costs per participant screened and enrolled to ensure trial accrual rates were achieved. We took the perspective of a healthcare system which may adopt, and possibly sustain, the strategy in the typical practice. We also estimated replication costs based on how the strategy could be applied in healthcare systems interested in referring patients to a local diabetes prevention program from a payer perspective. In this case, we examined differences in cost based on requirements for and types of, glucose testing, and by labor activities and non-labor resources associated with recruitment using sensitivity analyses. Results The total recruitment and enrollment costs were $389,949 to accrue 599 participants over approximately 15 months. The average cost per screened and enrolled participant was $276 and $651, respectively. Primary costs included hemoglobin A1c testing ($83,106), recruitment screening calls ($48,791), and personnel time ($96,187). Translating to the typical settings, total recruitment costs for replication was estimated as $192,625 (range: $42,523-$208,876). Sensitivity analysis results indicated replication costs would be approximately $229 - $430 per patient enrolled if glucose testing was necessary, based on the Medicare covered services. For a private payer perspective, and without glucose testing, per-participant screening and enrollment costs were estimated at $30. Conclusions A PHM approach can be used to accrue a large number of participants in a short period of time for an HEI trial, at a comparable cost per participant. However, when trial requirements are removed and PHM approaches are used as a method for healthcare systems to identify and enroll patients in a local program—the costs are relatively low.

Instrumental (operant) behavior can be goal directed, but after extended practice it can become a habit triggered by environmental stimuli. There is little information, however, about the variables that encourage habit learning, or about the development of discriminated habits that are actually triggered by specific stimuli. (Most studies of habit in animal learning have used free-operant methods.) In the present experiments, rats received training in which a lever press was reinforced only in the presence of a discrete stimulus (S) and the status of the behavior as goal-directed or habitual was determined by reinforcer devaluation tests. Experiment 1 compared lever insertion and an auditory cue (tone) in their ability to support habit learning. Despite prior speculation in the literature, the "salient" lever insertion S was not better than the tone at supporting habit, although the rats learned more rapidly to respond in its presence. Experiment 2 then examined the role of reinforcer predictability with the brief (6-s) tone S. Lever pressing during the tone was reinforced on either every trial or on 50% of trials; habit was observed only with the highly predictable (100%) relationship between S and the reinforcer. Experiment 3 replicated this effect with the tone in a modified procedure and found that lever insertion contrastingly encouraged habit regardless of reinforcer predictability. The results support an interactive role for reinforcer predictability and stimulus salience in discriminated habit learning. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

SYNGAP1haploinsufficiency in humans causes intellectual disability (ID). SYNGAP1 is highly expressed in cortical excitatory neurons and, reducing its expression in mice accelerates the maturation of excitatory synapses during sensitive developmental periods, restricts the critical period window for plasticity, and impairs cognition. However, its specific role in interneurons remains largely undetermined. In this study, we investigated the effects of conditionalSyngap1disruption in medial ganglionic eminence (MGE)-derived interneurons on hippocampal interneuron firing properties and excitatory synaptic inputs, as well as on pyramidal cell synaptic inhibition and synaptic integration. We show that conditionalSyngap1disruption in MGE-derived interneurons results in cell-specific impairment of firing properties of hippocampal Nkx2.1 fast-spiking interneurons, with enhancement of their AMPA receptor (AMPAR)-mediated excitatory synaptic inputs but compromised short-term plasticity. In contrast, regular-spiking Nkx2.1 interneurons are largely unaffected. These changes are associated with impaired pyramidal cell synaptic inhibition and enhanced summation of excitatory responses. Unexpectedly, we found that theSyngap1floxallele used in this study contains inverted loxP sites and that its targeted recombination in MGE-derived interneurons induces some cell loss during embryonic development and the reversible inversion of the sequence flanked by the loxP sites in postmitotic cells. Together, these results suggest thatSyngap1plays a role in cell-specific regulation of hippocampal interneuron function and inhibition of pyramidal cells in mice. However, because of our finding that theSyngap1floxallele used in this study contains inverted loxP sites, it will be important to further investigate interneuron function using a differentSyngap1conditional allele.

Purpose: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. Methods: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. Results: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators’ recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. Conclusion: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

ObjectivesTo identify existing evidence concerning the cost of dissemination and implementation (D&I) strategies in community, public health and health service research, mapped with the ‘Expert Recommendations for Implementing Change’ (ERIC) taxonomy.DesignScoping review.Data sourcesMEDLINE, EMBASE, CINAHL, PsycINFO, Scopus and the Cochrane Library were searched to identify any English language reports that had been published between January 2008 and December 2019 concerning the cost of D&I strategies.Data extractionWe matched the strategies identified in each article using ERIC taxonomies; further classified them into five areas (eg, dissemination, implementation, integration, capacity building and scale-up); and extracted the corresponding costs (total costs and cots per action target and per evidence-based programme (EBP) participant). We also recorded the reported level of costing methodology used for cost assessment of D&I strategies.ResultsOf the 6445 articles identified, 52 studies were eligible for data extraction. Lack of D&I strategy cost data was the predominant reason (55% of the excluded studies) for study exclusion. Predominant topic, setting, country and research design in the included studies were mental health (19%), primary care settings (44%), the US (35%) and observational (42%). Thirty-five (67%) studies used multicomponent D&I strategies (ranging from two to five discrete strategies). The most frequently applied strategies were Conduct ongoing training (50%) and Conduct educational meetings (23%). Adoption (42%) and reach (27%) were the two most frequently assessed outcomes. The overall costs of Conduct ongoing training ranged from $199 to $105 772 ($1–$13 973 per action target and $0.02–$412 per EBP participant); whereas the cost of Conduct educational meetings ranged from $987 to $1.1–$2.9 million/year ($33–$54 869 per action target and $0.2–$146 per EBP participant). The wide range of costs was due to the varying scales of the studies, intended audiences/diseases and the complexities of the strategy components. Most studies presented limited information on costing methodology, making interpretation difficult.ConclusionsThe quantity of published D&I strategy cost analyses is increasing, yet guidance on conducting and reporting of D&I strategy cost analysis is necessary to facilitate and promote the application of comparative economic evaluation in the field of D&I research.

Advances in genomics have transformed our ability to identify the genetic causes of rare diseases (RDs), yet we have a limited understanding of the mechanistic roles of most genes in health and disease. When a novel RD gene is first discovered, there is minimal insight into its biological function, the pathogenic mechanisms of disease-causing variants, and how therapy might be approached. To address this gap, the Canadian Rare Diseases Models and Mechanisms (RDMM) Network was established to connect clinicians discovering new disease genes with Canadian scientists able to study equivalent genes and pathways in model organisms (MOs). The Network is built around a registry of more than 500 Canadian MO scientists, representing expertise for over 7,500 human genes. RDMM uses a committee process to identify and evaluate clinician-MO scientist collaborations and approve 25,000 Canadian dollars in catalyst funding. To date, we have made 85 clinician-MO scientist connections and funded 105 projects. These collaborations help confirm variant pathogenicity and unravel the molecular mechanisms of RD, and also test novel therapies and lead to long-term collaborations. To expand the impact and reach of this model, we made the RDMM Registry open-source, portable, and customizable, and we freely share our committee structures and processes. We are currently working with emerging networks in Europe, Australia, and Japan to link international RDMM networks and registries and enable matches across borders. We will continue to create meaningful collaborations, generate knowledge, and advance RD research locally and globally for the benefit of patients and families living with RD.

The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of Sim1-expressing neurons critical for feeding regulation. Sim1 haploinsufficiency results in hyperphagic obesity with disruption of PVH neurons, yet the molecular profiles of PVH neurons and the mechanism underlying the defects of Sim1 haploinsufficiency are not well understood. By single-cell RNA sequencing, we identified two major populations of Sim1+ PVH neurons, which are differentially affected by Sim1 haploinsufficiency. The Iroquois homeobox genes Irx3 and Irx5 have been implicated in the hypothalamic control of energy homeostasis. We found that Irx3 and Irx5 are ectopically expressed in the Sim1+ PVH cells of Sim1+/− mice. By reducing their dosage and PVH-specific deletion of Irx3, we demonstrate that misexpression of Irx3 and Irx5 contributes to the defects of Sim1+/− mice. Our results illustrate abnormal hypothalamic activities of Irx3 and Irx5 as a central mechanism disrupting PVH development and feeding regulation in Sim1 haploinsufficiency.

Description, Irx3 and Irx5 misexpression in paraventricular nucleus of the hypothalamus leads to hyperphagic obesity in Sim1 haploinsufficiency., The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of Sim1-expressing neurons critical for feeding regulation. Sim1 haploinsufficiency results in hyperphagic obesity with disruption of PVH neurons, yet the molecular profiles of PVH neurons and the mechanism underlying the defects of Sim1 haploinsufficiency are not well understood. By single-cell RNA sequencing, we identified two major populations of Sim1+ PVH neurons, which are differentially affected by Sim1 haploinsufficiency. The Iroquois homeobox genes Irx3 and Irx5 have been implicated in the hypothalamic control of energy homeostasis. We found that Irx3 and Irx5 are ectopically expressed in the Sim1+ PVH cells of Sim1+/− mice. By reducing their dosage and PVH-specific deletion of Irx3, we demonstrate that misexpression of Irx3 and Irx5 contributes to the defects of Sim1+/− mice. Our results illustrate abnormal hypothalamic activities of Irx3 and Irx5 as a central mechanism disrupting PVH development and feeding regulation in Sim1 haploinsufficiency.

Background: The relevance of social support for weight management is not well documented in people with prediabetes. An important consideration is the adequate assessment of social provisions related to weight management in this population.Purpose: To assess the factor structure and measurement invariance of an adapted Social Provisions Scale specific to weight management (SPS-WM) in adults with prediabetes (n=599).Methods: Participants of a diabetes prevention trial completed a demographic survey, and the SPS-WM. Confirmatory analyses tested the factor structure of the SPS-WM, and measurement invariance was assessed for gender, weight status, education level, and age.Results: Removal of two collinear items resulted in acceptable model fit, supporting six correlated factors for social provisions specific to weight management. Measurement invariance was supported across all subgroups.Conclusion: Results support score interpretations for these scales reflecting distinct components of social support specific to weight management in alignment with those of the original survey.

Neonatal progeroid syndrome, also known as Wiedemann–Rautenstrauch syndrome, is a rare condition characterized by severe growth retardation, apparent macrocephaly with prominent scalp veins, and lipodystrophy. It is caused by biallelic variants in POLR3A, a gene encoding for a subunit of RNA polymerase III. All variants reported in the literature lead to at least a partial loss-of-function (when considering both alleles together). Here, we describe an individual with several clinical features of neonatal progeroid syndrome in whom exome sequencing revealed a homozygous nonsense variant in POLR3GL (NM_032305.2:c.358C>T; p.(Arg120Ter)). POLR3GL also encodes a subunit of RNA polymerase III and has recently been associated with endosteal hyperostosis and oligodontia in three patients with a phenotype distinct from the patient described here. Given the important role of POLR3GL in the same complex as the protein implicated in neonatal progeroid syndrome, the nature of the variant identified, our RNA studies suggesting nonsense-mediated decay, and the clinical overlap, we propose POLR3GL as a gene causing a variant of neonatal progeroid syndrome and therefore expand the phenotype associated with POLR3GL variants.

Objectives: The objectives of our study were to (1) illustrate a public health workforce assessment process in a medium-sized city or county health department and (2) demonstrate the insights gained by moving from the use of aggregate department-level and competency domain-level training needs results to more granular division-level and skills-level results when creating a workforce development plan. Methods: We used a 130-question needs assessment to guide the creation of a workforce development plan for the Lincoln Lancaster County Health Department (LLCHD) in Nebraska and its 7 divisions. Using SurveyMonkey, we administered the survey to 128 (of the 129) LLCHD public health staff members in June 2015. Using a Likert scale, respondents indicated (1) the importance of the skill to their work and (2) their capacity to carry out 57 skills in 8 domains of the core competencies for public health professionals. We identified training needs as those for which the percentage of respondents who perceived moderate-to-high importance was at least 15 percentage points higher than the percentage of respondents who perceived moderate-to-high capacity. Results: LLCHD as a department had training needs in only 2 competency domains: financial planning and management (importance-capacity difference, 15 percentage points) and policy development and program planning (importance-capacity difference, 19 percentage points). The Health Promotion and Outreach division had training needs in all 8 domains (importance-capacity difference range, 15-45 percentage points). Of the 57 skills, 41 were identified by at least 1 of the LLCHD divisions as having training needs. In 24 instances, a division did not qualify as having training needs in the overall domain yet did have training needs for specific skills within a domain. Conclusions: When performing public health workforce assessments, medium-to-large public health departments can obtain detailed workforce training needs results that pertain to individual skills and that are tailored to each of their divisions. These results may help customize and improve workforce development plans, ensuring that the workforce has the necessary skills to do its job.

Background Cost-effectiveness acceptability curves (CEACs) and the cost-effectiveness acceptability frontier (CEAF) are the recommended graphical representations of uncertainty in a cost-effectiveness analysis (CEA). Nevertheless, many limitations of CEACs and the CEAF have been recognized by others. Expected loss curves (ELCs) overcome these limitations by displaying the expected foregone benefits of choosing one strategy over others, the optimal strategy in expectation, and the value of potential future research all in a single figure. Objectives To revisit ELCs, illustrate their benefits using a case study, and promote their adoption by providing open-source code. Methods We used a probabilistic sensitivity analysis of a CEA comparing 6 cerebrospinal fluid biomarker test-and-treat strategies in patients with mild cognitive impairment. We showed how to calculate ELCs for a set of decision alternatives. We used the probabilistic sensitivity analysis of the case study to illustrate the limitations of currently recommended methods for communicating uncertainty and then demonstrated how ELCs can address these issues. Results ELCs combine the probability that each strategy is not cost-effective on the basis of current information and the expected foregone benefits resulting from choosing that strategy (ie, how much is lost if we recommended a strategy with a higher expected loss). ELCs display how the optimal strategy switches across willingness-to-pay thresholds and enables comparison between different strategies in terms of the expected loss. Conclusions ELCs provide a more comprehensive representation of uncertainty and overcome current limitations of CEACs and the CEAF. Communication of uncertainty in CEA would benefit from greater adoption of ELCs as a complementary method to CEACs, the CEAF, and the expected value of perfect information.

In light of the need to expand the reach and access of clinically proven digital Diabetes Prevention Programs (d-DPPs) and the need for rigorous evidence of effectiveness, the purpose of this study was to determine the effectiveness of a digital Diabetes Prevention Program for improving weight, HbA1c, and cardiovascular risk factors among people with prediabetes compared to enhanced standard care plus waitlist control.This was a single-blind RCT among participants at risk of developing type 2 diabetes and included 12 months of follow-up.A total of 599 volunteer patients with prediabetes were recruited primarily through electronic medical records and primary care practices.Participants were randomized to either a d-DPP (n=299) or a single-session small-group diabetes-prevention education class (n=300) focused on action planning for weight loss. The d-DPPs consisted of 52 weekly sessions, lifestyle coaching, virtual peer support, and behavior tracking tools.The primary outcome was a change in HbA1c from baseline to 12 months using intent-to-treat analyses. On the basis of multiple comparisons of endpoints, 95% CIs are presented and 2-sided p0.025 was required for statistical significance. Secondary outcomes included body weight and cardiovascular disease risk factors.Among 599 randomized participants (mean age=55.4 years, 61.4% women), 483 (80%) completed the study. The d-DPPs produced significantly greater reductions in HbA1c (0.08%, 95% CI= -0.12, -0.03) and percentage change in body weight (-5.5% vs -2.1%, p0.001) at 12 months. A greater proportion of the d-DPPs group achieved a clinically significant weight loss ≥5% (43% vs 21%, p0.001), and more participants shifted from prediabetes to normal HbA1c range (58% vs 48%, p=0.04). Engagement in d-DPPs was significantly related to improved HbA1c and weight loss.This d-DPPs demonstrated clinical effectiveness and has significant potential for widespread dissemination and impact, particularly considering the growing demand for telemedicine in preventive healthcare services.This study is registered at www.gov (ClinicalTrials.gov Identifier: NCT03312764).

Population health management (PHM) strategies to address diabetes prevention have the potential to engage large numbers of at-risk individuals in a short duration. We examined a PHM approach to recruit participants to a diabetes prevention clinical trial in a metropolitan health system. We examined reach and representativeness and assessed differences from active and passive respondents to recruitment outreach, and participants enrolled through two clinical screening protocols. The PHM approach included an electronic health record (EHR) query, physician review of identified patients, letter invitation, and telephone follow-up. Data describe the reach and representativeness of potential participants at multiple stages during the recruitment process. Subgroup analyses examined proportional reach, participant differences based on passive versus active recruitment response, and clinical screening method used to determine diabetes risk status. The PHM approach identified 10,177 potential participants to receive a physician letter invitation, 60% were contacted by telephone, 2,796 (46%) completed telephone screening, 1,961 were eligible from telephone screen, and 599 were enrolled in 15 months. Accrual was unaffected by shifting clinical screening protocols despite the increase in participant burden. Relative to census data, study participants were more likely to be obese, female, older, and Caucasian. Relative to the patient population, enrolled participants were less likely to be Black and were older. Active respondents were more likely to have a higher income than passive responders. PHM strategies have the potential to reach a large number of participants in a relatively short period, though concerted efforts are needed to increase participant diversity.

Objectives Insomnia is a common problem affecting young adult cancer survivors (YACS) even years after treatment, yet it often goes unidentified and untreated. The Insomnia Severity Index is a widely-used insomnia measure, but has not been studied as an insomnia screener for YACS. The goal of this study was to validate the ISI in YACS by determining its utility in identifying YACS with insomnia disorder diagnosed with the Structured Clinical Interview for the DSM-5 (SCID-5). Methods 250 YACS completed the ISI and SCID-5 Insomnia Module. Area under the curve (AUC) was calculated to reflect the ISI's discrimination between YACS with and without SCID-5 insomnia disorder. An ISI cut-off score with sensitivity ≥0.85 and specificity ≥0.75 was deemed acceptable. Results Of 250 participants, 52 met criteria for SCID-5 insomnia disorder diagnosis. The ISI had excellent discrimination, with an AUC = 0.91. A cut-off score ≥8 met study clinical screening criteria with sensitivity of 0.85 and specificity of 0.77. A cut-off score ≥7 with a higher sensitivity (0.96) but lower specificity (0.70) was noted as a potential alternative. Cut-off scores ≥12 and ≥ 14 were recommended for applications prioritizing overall accuracy. Conclusions Results support validity of the ISI for identifying YACS with insomnia disorder. For clinical screening, data support the use of an ISI cut-off score ≥8 in YACS, and additional cut-off scores were found for research purposes or higher sensitivity. Results of this study and prior studies of the ISI offer important reminders that cut-off scores derived from different populations are not generalizable.

BackgroundHigh-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).MethodsThis study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28).ResultsA total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.ConclusionOur study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.

Black men experience higher levels of chronic stress, life stressors, and discrimination due to oppressive social and economic conditions. Black men are at greater risk of depression, but most published research on stress and depression has focused on Black people in general, Black women, or older Black men. We sought to determine whether discrimination, perceived stress, major life stress, daily hassles, and social capital were associated with depressive symptoms in young Black men. Survey data were collected from April 2010 to March 2012 in Southern California from a convenience sample of Black men ( N = 201). We used two-sample t tests and one-way analysis of variance (ANOVA) to examine the association of stress correlates with depressive symptoms. Logistic regression was conducted to estimate the likelihood of reporting depressive symptoms for each significant correlate. Over half of the sample reported depressive symptoms. Health status, perceived discrimination, urban hassles, perceived stress, and neighborhood trust and safety were significantly related to depressive symptoms. Those who reported higher perceived stress had higher odds of reporting depressive symptoms, whereas lower everyday discrimination experiences were associated with lower odds of depressive symptoms. Future studies should consider examining the effectiveness of embedding coping mechanisms for stress, including perceived discrimination, in health interventions for young Black men to prevent or reduce depression.

Chromosome 1q41-q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41-q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41-q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41-q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders.

The purpose of this investigation was to understand perspectives of physicians, nurses, and staff regarding the feasibility of implementing an evidence-based weight management program to support primary care practice. An exploratory aim was to examine differences in responses based on the clinic location. Ten focus groups were conducted with primary care staff from rural, micropolitan, and metropolitan clinics. The Promoting Action on Research in Health Services (PARIHS) framework was used to inform the interview guide. Transcripts were reviewed to identify common themes among PARIHS constructs (evidence, context, and facilitation). Presence of comorbidities (e.g., diabetes, hypertension) were typical prompts for provider-led discussions about patient weight. Metropolitan clinics reported the availability of health coaching, diabetes education, or dietician consultation, but no clinic reported offering a comprehensive weight management program. Participants agreed it is possible to implement a weight management program through primary care, but cited potential facilitation challenges such as costs, clinic resources, and individual patient barriers. More enthusiasm arose for a referral program with patient tracking. Program characteristics such as proven efficacy, individual tailoring, program accessibility, and patient feedback to the providers were desired. Rural focus group participants reported unique barriers (lack of local resources) and facilitators (more flexibility in practice changes) to weight management when compared to metropolitan and micropolitan focus groups. Primary care staff are interested in weight management solutions for their patients and would prefer an evidence-based program to which they could refer patients, receive feedback on patient progress, and sustainably include as part of their regular services.

Background High attrition following initial enrollment in evidence-based weight loss programs is a common, challenging, and under-studied issue. A behavioral economics approach consisting of modest monetary incentives may help to engage participants beyond enrollment to close the initial attrition gap. Purpose To describe the methods and design of a pragmatic, online randomized controlled trial (RCT) of an incentivized, technology-facilitated weight loss program through an innovative research-practice partnership involving primary care, health promotion researchers, and a small business. Methods This study is a four-arm (1:1:1:1) RCT that compares the efficacy of outcome-based (weight loss), process-based (weighing in), a combination of outcome- and process-based, or choice-based incentives on sustaining program reach after initial enrollment for an evidence-based weight loss program. The multicomponent weight loss program includes a website, social cognitive theory-based daily health coaching, tailored messaging delivered via email and text messaging, access to online health coaches, and objective weight assessment through a community kiosk. The study will enroll 400 individuals aged 19 and older who have a body mass index ≥25 kg/m2, and have reliable access to the Internet or a smart phone. Participants will be followed for 3, 6, 9, and 12 months to assess program reach and representativeness, and continued participation after enrollment. The secondary outcomes include weight loss and program implementation costs. We will conduct participant focus groups to understand the barriers and facilitators of participation and key informant interviews focusing on clinic managers and care providers to explore the potential for future adoption and implementation of the evidence-based program. Discussion This study possesses the potential to close the attrition gap after initial enrollment in a web-based digital weight loss intervention in the primary care and community settings. Clinicaltrials.gov registration: NCT04225234 .

This study aims to decipher the role of short tandem repeats (STRs) in epilepsy patients. Whole genome short-read sequencing data of 734 epileptic patients was used to look for known STR expansions associated with increased risk of neurodevelopmental diseases or epilepsy using three different software. Results show one hit of particular interest onARXgene associated with Early Infantile Encephalopathic Epilepsy that could be causal for one patient with developmental and epileptic encephalopathy. However, we show that the different software do not agree on most of the calls above the threshold and that experimental validation is still needed for diagnostic, although these algorithms could prove useful for pre-selection of samples to be validated.

Additional file 1 Table S1. Pearson’s Chi2 test of heterogeneity in prevalence of reported diseases with associated 95% confidence interval across occupationsa among male workers deceased by suicide (SNC, 1990–2014)

International audience; Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

Additional file 2 Table S2. Pearson’s Chi2 test of heterogeneity in prevalence of reported diseases with associated 95% confidence interval across occupational groupsa among female workers deceased by suicide (SNC, 1990–2014)

Background Association between high adiposity and the clinical progression of dementia remains puzzling. Objective To separately examine the association between body mass index (BMI) and cognitive, functional, and behavioral declines before, at, and after diagnosis of dementia, and further stratified by age groups, and sex. Methods A total of 1,141 individuals with incident dementia were identified from the Uniform Data Set of the National Alzheimer's Coordinating Center. Cognitive function was evaluated by Mini-Mental State Exam, functional abilities were assessed using Functional Activities Questionnaire, and behavioral symptoms were captured by Neuropsychiatric Inventory Questionnaire at each follow-up visit. We used separate linear-mixed effects models to examine the association. Results Compared to moderate baseline BMI, high baseline BMI was associated with 0.30-point slower annual progression rates in functional decline. For individuals aged 76 and over, high baseline BMI was associated with 0.42-point faster progression rates in cognitive decline annually. A U-shaped association between baseline BMI and cognitive decline was observed among men. Conclusion BMI levels before dementia diagnosis may facilitate the identification of different risk profiles for progression rates of cognitive and functional declines in individuals who developed dementia.

Transposable elements modify human genome by inserting into new loci or by mediating homology-, microhomology-, or homeology-driven DNA recombination or repair, resulting in genomic structural variation. Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare, lethal, neonatal developmental lung disorder caused by point mutations or copy-number variant (CNV) deletions of FOXF1 or its distant tissue-specific enhancer. Eighty five per cent of 45 ACDMPV-causative CNV deletions, of which junctions have been sequenced, had at least one of their two breakpoints located in a retrotransposon, with more than half of them being Alu elements. We describe a novel ~35 kb-large genomic instability hotspot at 16q24.1, involving two evolutionarily young LINE-1(L1) elements, L1PA2 and L1PA3, flanking AluY, two AluSx, AluSx1, and AluJr elements. The occurrence of L1s at this location coincided with the branching out of the Homo-Pan-Gorilla clade, and was preceded by the insertion of AluSx, AluSx1, and AluJr. Our data show that, in addition to mediating recurrent CNVs, L1 and Alu retrotransposons can predispose the human genome to formation of variably sized CNVs, both of clinical and evolutionary relevance. Nonetheless, epigenetic or other genomic features of this locus might also contribute to its increased instability.