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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.

Objective Altered sensory processing is common in intellectual disability (ID). Here, we study electroencephalographic responses to auditory stimulation in human subjects presenting a rare condition (mutations in SYNGAP1) which causes ID, epilepsy and autism. Methods Auditory evoked potentials, time-frequency and inter-trial coherence analyses were used to compare subjects with SYNGAP1 mutations with Down syndrome (DS) and neurotypical (NT) participants (N = 61 ranging from three to 19 years of age). Results Altered synchronization in the brain responses to sound were found in both ID groups. The SYNGAP1 mutations group showed less phase-locking in early time windows and lower frequency bands compared to NT, and in later time windows compared to NT and DS. Time-frequency analysis showed more power in beta-gamma in the SYNGAP1 group compared to NT participants. Conclusions This study indicated reduced synchronization as well as more high frequencies power in SYNGAP1 mutations, while maintained synchronization was found in the DS group. These results might reflect dysfunctional sensory information processing caused by excitation/inhibition imbalance, or an imperfect compensatory mechanism in SYNGAP1 mutations individuals. Significance Our study is the first to reveal brain response abnormalities in auditory sensory processing in SYNGAP1 mutations individuals, that are distinct from DS, another ID condition.

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.

Introduction: Despite growing documentation of the efficacy of telemedicine in diabetes management, racial disparities in telemedicine-facilitated diabetes management remain underexplored. This study examined disparities in diabetes management outcomes between black and white patients with type 2 diabetes (T2D) in a remote monitoring program. Methods: The analysis sample included 914 white T2D patients and 365 black T2D patients in Nebraska who completed a 3-month remote patient monitoring and coaching after hospital discharge from 2014 to 2017. Ordinary least squares regression was estimated to examine racial differences in hemoglobin A1c (HbA1c), and logistic regression was used to determine the odds of HbA1c > 9% at the end of the program, controlling for demographics, baseline health conditions, and patient activation and engagement with the program. Results: The proportion of white patients with HbA1c > 9% was reduced from 16% at the baseline to 7% at program completion, and the corresponding reduction among black patients was from 30% to 18%. After adjusting for the effects of baseline HbA1c and other covariates, the average HbA1c among black patients at the end of the program was 0.23 points higher than that among white patients (p 9% was 1.68 times that of white patients (95% confidence interval [1.07-2.63]). Discussion: The remote patient monitoring and coaching program reduced the absolute gap between black and white T2D patients. However, substantial racial disparities in HbA1c still remained at the end of the program and warranted further research.

The primary function of the patient portal is to give patients greater access to their personal health information. Granting patients electronic access allows them to make well-informed health care decisions. This study aimed to identify sociodemographic differences in patient portal use and examine factors affecting patient portal utilization following the final stage of the Meaningful Use program which aimed to promote the use of certified electronic health record (EHR) technology. Survey data from Health Information National Trends Survey (HINTS) 5, cycles 1, 2, and 3 were analyzed. The sample included 8291 completed surveys. Multivariable logistic regression on a selected response for each surveyed question was used to assess the racial and ethnic difference after controlling for age, sex, income, and education. Subjects included English and Spanish speaking adults in the USA. Measures included assessment of patient portal use, patient portal access, understanding health information, usefulness of health records, and privacy and security. After adjusting for age, sex, income, and education, there was a significant association between race/ethnicity and patient portal non-users responding, “no need to use online medical record” as the reason for not using the patient portal (P = 0.005). Among the portal users, there were significant associations between race/ethnicity and health care provider maintaining an EHR (P = 0.006), being offered access to their portal (P

Background: Evidence-based guidelines for the management of type 2 diabetes (T2D) consist of blood glucose monitoring, medication adherence, and lifestyle modifications that may particularly benefit from reminders, consultation, education, and behavioral reinforcements through remote patient monitoring (RPM). Objectives: To identify predictors of weight loss and to examine the association between weight loss and hemoglobin A1C (HbA1C) outcomes for T2D patients who were enrolled in an RPM program for diabetes management. Materials and Methods: The study applied logistic and ordinary least-squares regression models to examine the relationship between baseline characteristics and the likelihood of weight loss during the RPM, and how the magnitude of weight loss was related to changes in HbA1C outcomes for 1,103 T2D patients who went through 3 months of RPM from 2014 to 2017. Results: Older patients were 3% more likely to have weight loss (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.02-1.05), whereas patients with higher baseline HbA1C had 9% reduced odds (OR, 0.91; 95% CI, 0.85-0.97) of experiencing weight loss. For every pound of weight lost, there was a 0.02-point (95% CI, 0.01-0.03) reduction on the HbA1C measured at the end of the RPM. Moreover, compared with those who had weight loss of ≤3%, participants who had lost 5-7%, or >7% of their baseline weight had a 0.37- and 0.58-point reduction in HbA1C, respectively. Conclusions: This study revealed a notable relationship between weight loss and positive HbA1C outcomes for T2D patients in an RPM-facilitated diabetes management program, which pointed to the potential of integrating evidence-based lifestyle modification programs into future telemedicine programs to improve diabetes management outcomes.

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.

Background: Several family-based efficacious pediatric weight management interventions (PWMIs) have been developed to reduce child weight status. These programs are typically based in larger cities...

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.

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.

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.

Introduction: Lifestyle modification to promote regular physical activity and healthy eating is a key element of diabetes management. We aimed at evaluating randomized controlled trials that assess...

PURPOSE Pediatric oncology clinicians identify a need for increased sexual and reproductive health (SRH) education with adolescent and young adult (AYA) cancer patients. By surveying pediatric oncology fellowship directors, this study clarifies the state of current fellowship education about SRH for the AYA patient. METHODS A survey was sent to all pediatric oncology fellowship program directors (PDs) in the United States consisting of 13 questions pertaining to three primary SRH domains: sexual health, fertility, and safe sex practices. Descriptive statistics and χ2 were used in data analyses. RESULTS Sixty-three PDs responded to the survey (91% response rate). Of these, 88% reported having formal instruction regarding fertility, 41% reported curriculum regarding contraception and 30% reported some education regarding sexual health. The curriculum "being too full" was identified as a barrier to education on fertility (29%), sexual health (40%), and safe sex practices (38%). Not being a required or expected part of the program was more likely to be endorsed as a barrier for sexual health (26%) and safe sex practices (30%) compared with fertility (8%) (P

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.

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.

The objective of this study was to evaluate changes in clinical outcomes for patients with type 2 diabetes (T2D) after a 3-month remote patient monitoring (RPM) program, and examine the relationship between hemoglobin A1c (HbA1c) outcomes and participant characteristics. The study sample included 955 patients with T2D who were admitted to an urban Midwestern medical center for any reason from 2014 to 2017, and used RPM for 3 months after discharge. Clinical outcomes included HbA1c, weight, body mass index (BMI), and patient activation scores. Logistic regression was used to estimate the likelihood of having a postintervention HbA1c9% by patient characteristics, among those who had baseline HbA1c9%. Most patients experienced decreases in HbA1c (67%) and BMI (58%), and increases in patient activation scores (67%) (P 0.001 in all 3 cases) at the end of RPM. Logistic regression analyses revealed that among patients who had HbA1c9% at baseline, men (odds ratio [OR] = 3.72; 95% confidence interval [CI], 1.43-9.64), those who had increased patient activation scores after intervention (OR = 1.05; 95% CI, 1.01-1.09), those who had higher baseline patient activation scores, and those who had a greater number of biometric data uploads during the intervention (OR = 1.02; 95% CI, 1.00-1.04) were more likely to have reduced their HbA1c to9% at the end of RPM. RPM for postdischarge patients with T2D might be a promising approach for HbA1c control with increased patient engagement. Future studies with study designs that include a control group should provide more robust evidence.

Cervical cancer is preventable; however, despite the existence of primary and secondary means of prevention, its incidence is still higher in certain socioeconomic groups and countries, suggesting gaps in cervical cancer prevention. The objective of this study was to evaluate the knowledge and awareness of health sciences university students in Cyprus regarding HPV and cervical cancer in order to better guide the future development of educational programs to improve cervical cancer prevention. This was a cross-sectional study of 178 university health sciences students in Cyprus using a validated questionnaire on HPV and cervical cancer prevention. Analysis of the completed questionnaires revealed moderate levels of knowledge and awareness with an overall mean score of 23.32 out of 33 on HPV and 8.12 out of 13 on cervical cancer, a score of 9.25 out of 14 on HPV vaccines, and a score of 5.93 out of 9 on cervical cancer screening. Older students achieved higher scores compared to younger students (mean score of 6.76 for 18–22 years old, 9.44 for 23–28 years old, and 10.25 for 29–38 years old; p

Few data are available to describe the changes in incidence of pediatric-onset inflammatory bowel disease (IBD). The aim of this study was to describe changes in incidence and phenotypic presentation of pediatric-onset IBD in northern France during a 24-year period.Pediatric-onset IBD (17 years) was issued from a population-based IBD study in France between 1988 and 2011. Age groups and digestive location were defined according to the Paris classification.1,350 incident cases were recorded (8.3% of all IBD) including 990 Crohn's disease (CD), 326 ulcerative colitis (UC) and 34 IBD unclassified (IBDU). Median age at diagnosis was similar in CD (14.4 years (Q1=11.8-Q3=16.0)) and UC (14.0 years (11.0-16.0)) and did not change over time. There were significantly more males with CD (females/males=0.82) than UC (females/males=1.25) (P=0.0042). Median time between onset of symptoms and IBD diagnosis was consistently 3 months (1-6). Mean incidence was 4.4/10In this population-based study, CD and UC incidences increased dramatically in adolescents across a 24-year span, suggesting that one or more strong environmental factors may predispose this population to IBD.

Objectives:The aim of this study was to systematically investigate existing literature on the costs of home-based telemedicine programs, and to further summarize how the costs of these telemedicine programs vary by equipment and services provided.Methods:We undertook a systematic review of related literature by searching electronic bibliographic databases and identifying studies published from January 1, 2000, to November 30, 2017. The search was restricted to studies published in English, results from adult patients, and evaluation of home telemedicine programs implemented in the United States. Summarized telemedicine costs per unit of outcome measures were reported.Results:Twelve studies were eligible for our review. The overall annual cost of providing home-based telemedicine varied substantially depending on specific chronic conditions, ranging from USD1,352 for heart failure to USD206,718 for congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and diabetes as a whole. The estimated cost per-patient-visit ranged from USD24 for cancer to USD39 for CHF, COPD, or chronic wound care.Conclusions:The costs of home-based telemedicine programs varied substantially by program components, disease type, equipment used, and services provided. All the selected studies indicated that home telemedicine programs reduced care costs, although detailed cost data were either incomplete or not presented in detail. A comprehensive analysis of the cost of home-based telemedicine programs and their determinants is still required before the cost efficiency of these programs can be better understood, which becomes crucial for these programs to be more widely adopted and reimbursed.

Background Fragile X syndrome (FXS) is a neurodevelopmental genetic disorder causing cognitive and behavioural deficits. Repetition suppression (RS), a learning phenomenon in which stimulus repetitions result in diminished brain activity, has been found to be impaired in FXS. Alterations in RS have been associated with behavioural problems in FXS; however, relations between RS and intellectual functioning have not yet been elucidated. Methods EEG was recorded in 14 FXS participants and 25 neurotypical controls during an auditory habituation paradigm using repeatedly presented pseudowords. Non-phased locked signal energy was compared across presentations and between groups using linear mixed models (LMMs) in order to investigate RS effects across repetitions and brain areas and a possible relation to non-verbal IQ (NVIQ) in FXS. In addition, we explored group differences according to NVIQ and we probed the feasibility of training a support vector machine to predict cognitive functioning levels across FXS participants based on single-trial RS features. Results LMM analyses showed that repetition effects differ between groups (FXS vs. controls) as well as with respect to NVIQ in FXS. When exploring group differences in RS patterns, we found that neurotypical controls revealed the expected pattern of RS between the first and second presentations of a pseudoword. More importantly, while FXS participants in the ≤ 42 NVIQ group showed no RS, the > 42 NVIQ group showed a delayed RS response after several presentations. Concordantly, single-trial estimates of repetition effects over the first four repetitions provided the highest decoding accuracies in the classification between the FXS participant groups. Conclusion Electrophysiological measures of repetition effects provide a non-invasive and unbiased measure of brain responses sensitive to cognitive functioning levels, which may be useful for clinical trials in FXS. Electronic supplementary material The online version of this article (10.1186/s11689-018-9223-3) contains supplementary material, which is available to authorized users.

Background Rural residents are at high risk for obesity; however, little resources exist to address this disproportional burden of disease. Primary care may provide an opportunity to connect primary care patients with overweight and obesity to effective weight management programming. Objective The purpose of this study is to examine the utility of different physician referral and engagement processes for improving the reach of an evidence-based and technology-delivered weight management program with counseling support for rural primary care patients. Methods A total of 5 rural primary care physicians were randomly assigned a sequence of four referral strategies: point-of-care (POC) referral with active telephone follow-up (ATF); POC referral, no ATF; a population health registry–derived letter referral with ATF; and letter referral, no ATF. For registry-derived referrals, physicians screened a list of patients with BMI ≥25 and approved patients for participation to receive a personalized referral letter via mail. Results Out of a potential 991 referrals, 573 (57.8%) referrals were made over 16 weeks, and 98 (9.9%) patients were enrolled in the program (58/98, 59.2% female). Differences based on letter (485/991, 48.9%) versus POC (506/991, 51.1%) referrals were identified for completion (100% vs 7%; P Conclusions Letter referral with ATF appears to be the best option for enrolling a large number of patients in a digitally delivered weight management program; however, POC with ATF and letters without ATF yielded similar numbers at a lower cost. The best referral option is likely dependent on the best fit with clinical resources. Trial Registration ClinicalTrials.gov NCT03690557; http://clinicaltrials.gov/ct2/show/NCT03690557

This study assessed the lifetime health and economic consequences of an efficacious scalable community weight loss program for overweight and obese adults. We applied a state-transition Markov model to project lifetime economic outcome (US dollar) and the degree of disease averted as a result of a weight loss intervention, compared with no intervention, from a payer perspective. Effect sizes of the intervention on weight loss, by sex, race and ethnicity, and body mass index (BMI) of participants, were derived from a 12-month community program. Relative risk of diseases across BMI levels and other parameters were informed by the literature. A return on investment (ROI) analysis was conducted to present the overall cost-benefit of the program. Simulation results showed that among 33,656 participants and at a cost of $2.88 million, the program was predicted to avert (with a corresponding estimated medical costs saved of) 78 cases of coronary heart disease ($28 million), 9 cases of strokes ($971,832), 92 cases of type 2 diabetes ($24 million), 1 case of colorectal cancer ($357,022), and 3 cases of breast cancer ($483,259) over the participant lifetime. The estimated medical costs saved per participant was $1,403 ($1,077 of African American men and $1,532 of Hispanic men), and the ROI was $16.7 ($12.8 for African American men and $18.3 for Hispanic men) for every $1 invested. We concluded that a scalable efficacious community weight loss program provides a cost-effective approach with significant ROI, which will assist informed decisions for future adoption and dissemination.

BACKGROUND Sexual dysfunction is a distressing long-term effect after gynecological cancer and affects the majority of survivors for years after the completion of therapy. Despite its prevalence, treatment-related sexual dysfunction is underrecognized and undertreated for survivors. Thus, the aim of this study was to develop and test a brief psychoeducational intervention for managing sexual dysfunction for women who have undergone treatment for ovarian cancer (OC). METHODS Forty-six OC survivors with documented, treatment-related sexual dysfunction received a single half-day group intervention that included sexual health education and rehabilitation training, relaxation and cognitive behavioral therapy skills to address sexual symptoms, and a single tailored booster telephone call 4 weeks after the group. Assessment measures were completed at the baseline (baseline 1), after an 8-week no-treatment run-in period (baseline 2), and then again 2 and 6 months after the intervention. The Female Sexual Function Index (FSFI) was used to assess sexual functioning, and the Brief Symptom Inventory 18 (BSI-18) was used to capture psychological distress. RESULTS Between baseline 1 and baseline 2, there were no significant changes in the study measures, and this indicated no natural improvement during the run-in period. In contrast, the total FSFI scores improved significantly from baseline 1 to the 2- (n = 45; P

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.

Objective Cerebrospinal fluid (CSF) biomarkers are shown to facilitate a risk identification of patients with mild cognitive impairment (MCI) into different risk levels of progression to Alzheimer’s disease (AD). Knowing a patient’s risk level provides an opportunity for earlier interventions, which could result in potential greater benefits. We assessed the cost effectiveness of the use of CSF biomarkers in MCI patients where the treatment decision was based on patients’ risk level. Methods We developed a state-transition model to project lifetime quality-adjusted life-years (QALYs) and costs for a cohort of 65-year-old MCI patients from a US societal perspective. We compared four test-and-treat strategies where the decision to treat was based on a patient’s risk level (low, intermediate, high) of progressing to AD with two strategies without testing, one where no patients were treated during the MCI phase and in the other all patients were treated. We performed deterministic and probabilistic sensitivity analyses to evaluate parameter uncertainty. Results Testing and treating low-risk MCI patients was the most cost-effective strategy with an incremental cost-effectiveness ratio (ICER) of US$37,700 per QALY. Our results were most sensitive to the level of treatment effectiveness for patients with mild AD and for MCI patients. Moreover, the ICERs for this strategy at the 2.5th and 97.5th percentiles were US$18,900 and US$50,100 per QALY, respectively. Conclusion Based on the best available evidence regarding the treatment effectiveness for MCI, this study suggests the potential value of performing CSF biomarker testing for early targeted treatments among MCI patients with a narrow range for the ICER. Electronic supplementary material The online version of this article (doi:10.1007/s41669-017-0054-z) contains supplementary material, which is available to authorized users.

The level of assistance patients with Alzheimer’s disease (AD) require in their care may be an important predictor of resource use, costs of care and quality of life. The Dependence Scale (DS), a measure of care-assistance required, was used to estimate costs of care and quality of life of patients with AD categorized into six dependence stages based upon the summated item scores of the DS. Data was derived from a three-year, non-interventional study of 132 patients with probable AD (ages 50 to 85) and caregiver dyads. We investigated the association between DS scores and healthcare costs, health-related quality of life (HRQoL), caregiver burden and estimated annual costs and HRQoL for six dependence stages in adjusted models. DS scores were significant predictors of healthcare costs, HRQoL, and caregiver burden. The estimated annual healthcare costs and a measure of HRQoL (EuroQoL-5D) ranged from $11,418 and 1.00 for those at very mild dependence stage to $101,715 and 0.26 for those at very severe dependence stage. DS scores classified into six dependence stages provides a useful method to estimate unique levels of care-associated costs and health utilities for pharmacoeconomic evaluations of new treatments for AD.

Introduction There is a need for a precise and reliable imaging to improve the management of prostate cancer. In recent years the PET/CT with choline has changed the handling of prostate cancer in Europe, and it is commonly used for initial stratification or for the diagnosis of a biochemical recurrence, although it does not lack limitations. Other markers are being tested, including the ligand of prostate-specific membrane antigen (PSMA), that seems to offer encouraging prospects. The goal of this piece of work was to critically review the role of choline and PSMA PET/CT in prostate cancer. Evidence acquisition A systematic literature review of databases PUBMED/MEDLINE and EMBASE was conducted searching for articles fully published in English on the PET marker in prostate cancer and its clinical application. Evidence synthesis and discussion It seems as 68Ga-PSMA PET/CT is better than PET/CT in prostate cancer to detect primary prostate lesions, initial metastases in the lymph nodes and recurrence. However, further research is required to obtain high-level tests. Also, other PET markers are studied. Moreover, the emergence of a new PET/MR camera could change the performance of PET imaging.

Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect well-conserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p = 0.013) and 33% (p = 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options.

Background: It remains unclear how demographic and clinical characteristics are related to the risk of incident mild cognitive impairment (MCI) by its subtypes. Moreover, the contribution of the subtypes of incident MCI to the progression to dementia remains puzzling. Methods: We used data collected by the National Alzheimer Coordinating Center. Our analysis sample included cognitively normal subjects at baseline. The associations were examined using competing-risks survival regression models and Cox proportional hazards models. Results: About 16.3% of subjects developed incident MCI of whom 15.8% progressed to Alz­heimer disease (overall mean follow-up of 4.3 years). The risk of incident amnestic MCI (aMCI) was greater in subjects with 1 copy (subhazard ratio [SHR]: 1.23; 95% CI: 1.00–1.50) or 2 copies (SHR: 2.14; 95% CI: 1.49–3.05) of the APOE ε4 allele than in those who had no ε4 allele. Multiple-domain aMCI patients were more likely to progress to dementia than single-domain aMCI patients (hazard ratio: 2.14; 95% CI: 1.28–3.58). Conclusions: Cognitively normal subjects with an APOE ε4 allele had a higher likelihood of developing aMCI and the MCI subtype was associated with the dementia subtype. Our findings provide important information about practical indicators for the prediction of cognitive decline.

Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences., SCOPUS: ar.j, info:eu-repo/semantics/published

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Background Diabetes prevention remains a top public health priority; digital approaches are potential solutions to existing scalability and accessibility challenges. There remains a gap in our understanding of the relationship between effectiveness, costs, and potential for sustained implementation of digital diabetes prevention strategies within typical healthcare settings. Purpose To describe the methods and design of a type 1 hybrid effectiveness-implementation trial of a digital diabetes prevention program (DPP) using the iPARIHS and RE-AIM frameworks. Methods The trial will contrast the effects of two DPP interventions: (1) small group, in-person class, and (2) a digital DPP consisting of small group support, personalized health coaching, digital tracking tools, and weekly behavior change curriculum. Each intervention includes personal action planning with a focus on key elements of the lifestyle intervention from the CDC National DPP. Adults at risk for diabetes (BMI ≥25 and 5.7% ≤ HbA1c ≤ 6.4) will be randomly assigned to either the intervention group (n = 241) or the small group (n = 241). Assessment of primary (HbA1c) and secondary (weight loss, costs, cardiovascular risk factors) outcomes will occur at baseline, 4, and 12 months. Additionally, the trial will explore the potential for future adoption, implementation, and sustainability of the digitally-based intervention within a regional healthcare system based on key informant interviews and assessments of organizational administrators and primary care physicians. Conclusion This trial of a digital DPP will allow the research team to determine the relationships between reach, effectiveness, implementation, and costs.

Introduction With advances in surgical and neonatal care, survival of patients with esophageal atresia (EA) has improved over time. While a number of conditions associated with EA may have an impact on feeding development (delayed primary anastomosis, anastomotic leaks, recurrent tracheoesophageal fistula, anastomotic stricture, gastroesophageal reflux, esophageal dysmotility, etc.) and although children with EA experience a number of oral aversive events in their first year of life, feeding disorders (FD) are poorly described and frequently unrecognized. The primary aim of this study was to describe FD in children born with EA, with a standardized scale. The secondary aim was to describe conditions associated with FD. Methods FEED-EASY is a multicentric French study. Parents of children born with EA between 2013 and 2016 in one of the 22 participating centers were asked to participate and received the French version of the standardized and reproductive ‘Montreal Children's Hospital Feeding Scale (MCH-FS)’. Results One hundred and forty-five children were included; 61 (42%) had FD according to the MCH-FS. These children were characterized by disinterest in food, oral hypersensitivity, difficulty in touching some textures and food avoidance, with an influence in quality of life. Nineteen (13%) were tube-fed between 1 and 4 years of age. Birth weight and chronic respiratory difficulties were associated with FD in children with EA. Anastomotic stricture (present in 31% of the included children) was not associated with FD. Conclusions FD is frequent and unrecognized in children with EA, and can influence growth and quality of life. MCH-FS allows pediatricians to identify FD in children with EA within a couple of minutes.

Introduction Esophageal atresia (EA) is frequently associated with other malformations although few data are available. Objective Describe tracheobronchial, pulmonary and/or vascular malformations in patients with EA using chest CT scans. Methods Monocentric retrospective study in children with EA, born between 1996 and 2013, who had a CT scan during their follow-up, reviewed by a pediatric radiologist. Results Among 234 children with EA, 48 patients underwent a CT scan available for interpretation, among which 69% were performed to explore persistent respiratory symptoms. Thirty-nine children (81%) were type III EA, 13 (27%) had a VACTERL association. Six patients (13%) had a pulmonary malformation: 4 lobar agenesis, 1 right pulmonary aplasia, and 1 congenital cystic adenomatoid malformation. All these patients presented with at least one associated malformation. Combined with the results of laryngotracheal endoscopy (n = 30), 43 patients (90%) had a tracheobronchial anomaly: tracheomalacia for 40 (83%), tracheal stenosis for 12 (25%), right tracheal bronchus for 2 (4%), communicating bronchopulmonary foregut malformation for 1 (2%). Combined with the results of echocardiography (n = 47), 7 patients (15%) had an isolated vascular anomaly, 8 (17%) had an isolated congenital heart disease and 7 (15%) had both. CT scans permitted the diagnosis of 6 pulmonary malformations (13%), 15 tracheobronchial anomalies (31%), and 2 vascular anomalies (4%). Only one patient (2%) in our study presented with an isolated EA. Conclusion Our study confirms the association of tracheobronchial, pulmonary, and vascular anomalies in patients with EA. Contrast-enhanced CT scan is complementary to echocardiography and laryngotracheal endoscopy in the exploration of persistent respiratory symptoms.

Objectives and Study The aim of our study is to assess the risk factor of mortality and morbidity in a large population-based registry in a population of type III/C esophageal atresia (EA). Methods Under the umbrella of the national plan for rare disease, a population based register was set up in 2008 recording the data of all the live newborns with EA in France. Based on the registry data, survival and morbidity at 1 year were studied. Morbidity was approached by calculating the rate of full oral autonomy and the hospital length of stay during the first year. Multivariate analysis was performed via multinomial logistic regression to evaluate independent predictors of overall survival and morbidity items among all significant category variables identified on univariate analysis. Results A total of 1008 patients with type III EA were extracted from the national database born from January first 2008 till 31 December 2014. Mean birth weight was 2610 g (2060 to 3075). Right lateral thoracotomy was used in 93% of cases and primary anastomosis was possible in 95% of cases. Associated abnormalities were present in 53% of patients, VACTERL in 19%, and CHARGE syndrome in 3%. Mortality at 3 months was at 5% and at one year at 6% and was correlated to prenatal diagnosis (odd ratio (OR):2.96 (1.08 to 8.08)), low birth weight (OR: 0.52 (0.38 to 0.72)), and heart defect (OR: 6.09 (1.96 to 18.89)). Length of hospitalization was correlated to birth weight (OR: 0.83 (0.61–1.13)), the difficulty of the anastomosis (OR: 1.59 (0.71–3.55)) and associated abnormalities (OR: 1.93(0.65–5.68)), the prenatal diagnosis is correlated only to the rate of full oral autonomy and not with the length of hospitalization. Conclusions Surgical procedure or difficulties did not seem to affect survival in this group of patients. In addition to the continuous need to improve care of low weight neonates, our results clearly identify that efforts should be focused on the small group of EA with prenatal diagnosis and/or severe cardiac malformation to reduce even more mortality and morbidity in EA patients.

Objectives and study Anastomotic stricture (AS) is a frequent complication of the surgery for œsophageal atresia (OA) during the first year of life. The primary objective of this study was to evaluate the prevalence of AS before 1 year old in infants with type A and C OA who were operated on. Secondary objectives were to determine risk factors for AS in OA, for recurrent and refractory AS, and to establish if AS is associated with antireflux surgery. Methods A prospective national multicentric study was conducted including all infants born with OA between 2008 and 2015. Patients deceased before one year old, OA types B and E, and patients for whom data about AS were missing were excluded from the study. Data were collected at birth and at 12 months of age. Anastomosis under tension was defined by the surgeon and a delayed anastomosis was defined by an anastomosis after 15 days of life. Recurrent stricture was defined by the need of ≥3 dilations and refractory stricture was defined by the need of ≥5 dilations. Univariate and multivariate statistical analyses were conducted. Results Of the 1258 eligible patients (84%), 1054 were included in the study from 38 centers. The prevalence of AS in the first year of life was 23.3% [20.7–28.9]. Anastomosis under tension (AUT) and delayed anastomosis (DA) were found to be independent risk factors for AS (respectively 2.5 [1.73–3.45] and 3.7 [1.95–7.2] (OR [CL 95%])) in the total population. Neither sex, birth weight, prematurity, intrauterine growth retardation, associated malformations, type A OA, nor the type of surgical approach was a risk factor for AS. In type C OA, DA was the only risk factor for AS (OR: 3.1 [1.65–5.86]). The group with AS had 2.5-fold more fundoplication compared to the patients without AS (P = 0.0005) in the total population and in type C OA. AUT and DA were found to be independent risk factors for recurrent stricture (OR: 2.4 [1.47–3.9] and 4.7 [2.2–10.4], respectively) and DA was the only risk factor for refractory stricture (OR: 6.23 [2.4–16.2]). Conclusion Surgical factors at the time of first repair of OA are the only risk factors for AS.