The interaction between enhancer variants and environmental factors as an overlooked aetiological paradigm in human complex disease.

The interactions between genetic and environmental risk factors contribute to the aetiology of complex human diseases. Genome-wide association studies (GWAS) have revealed that most of the genetic variants associated with complex diseases are located in the non-coding part of the genome, preferentially within enhancers. Enhancers are distal cis-regulatory elements composed of clusters of transcription factors binding sites that positively regulate the expression of their target genes. The generation of genome-wide maps for histone marks (e.g., H3K27ac), chromatin accessibility and transcription factor and coactivator (e.g., p300) binding profiles have enabled the identification of enhancers across many human cell types and tissues. Nonetheless, the functional and pathological consequences of the majority of disease-associated genetic variants located within enhancers seem to be rather minor under normal conditions, thus questioning their medical relevance. Here we propose that, due to the prevalence of enhancer redundancy, the pathological effects of many disease-associated non-coding genetic variants might be preferentially (or even only) manifested under environmental stress.

Construction and Validation of an Individual Deprivation Index: a Study Based on a Representative Cohort of the Paris Metropolitan Area.

The association between health status and deprivation is well established. However, it is difficult to measure deprivation at an individual level and already-existing indices in France are not validated or do not meet the needs of health practitioners. The aim of this work was to establish a validated, easy-to-use, multidimensional, relevant index that was representative of the population in the Paris metropolitan area. From the SIRS 2010 cohort study, 14 socio-economic characteristics were selected: health insurance, educational background, socio-professional category, professional status, feelings of loneliness, emotional situation, household type, income, perceived financial situation, social support (support in daily life, financial and emotional), housing situation, and migration origin. In addition, a total of 12 health status, healthcare use, and nutrition-related variables were also selected. Content validity and internal validity of the index were explored. The 14 socio-economic indicators were associated to varying degrees with poorer health status, less use of healthcare, and poorer nutrition and were distributed across the 14 multiple-choice questions of the index. Each answer was rated from 0 to 2. The index value of 10 that isolates 20% of the most deprived individuals was used as threshold. "Being deprived," as defined with this value, was significantly associated with 9 of the 12 studied health variables. This index could be a relevant instrument in the assessment of deprivation and social inequalities of health.

Development of Primary Care Research in North America, Europe, and Australia From 1974 to 2017.

Research is a necessity for high-quality medicine. We used the MEDLINE database to conduct a bibliometric analysis of research output with respect to primary care by 21 countries. For the period 1974 to 2017, the United States and the United Kingdom stood out in terms of publication volume, and the UK, Canada, and Australia had the greatest percentage of publications in primary care. As of 2017, publications in primary care represented a small proportion of total publications. The countries with the greatest publication productivity possess factors that should be considered with respect to strengthening research in primary care.

Factors influencing the quality of life of pregnant women: a systematic review.

BACKGROUND: Pregnancy is a period of transition with important physical and emotional changes. Even in uncomplicated pregnancies, these changes can affect the quality of life (QOL) of pregnant women, affecting both maternal and infant health. The objectives of this study were to describe the quality of life during uncomplicated pregnancy and to assess its associated socio-demographic, physical and psychological factors in developed countries. METHODS: A systematic review was performed according to the PRISMA guidelines. Searches were made in PubMed, EMBASE and BDSP (Public Health Database). Two independent reviewers extracted the data. Countries with a human development index over 0.7 were selected. The quality of the articles was evaluated on the basis of the STROBE criteria. RESULTS: In total, thirty-seven articles were included. While the physical component of QOL decreased throughout pregnancy, the mental component was stable and even showed an improvement during pregnancy. Main factors associated with better QOL were mean maternal age, primiparity, early gestational age, the absence of social and economic problems, having family and friends, doing physical exercise, feeling happiness at being pregnant and being optimistic. Main factors associated with poorer QOL were medically assisted reproduction, complications before or during pregnancy, obesity, nausea and vomiting, epigastralgia, back pain, smoking during the months prior to conception, a history of alcohol dependence, sleep difficulties, stress, anxiety, depression during pregnancy and sexual or domestic violence. CONCLUSIONS: Health-related quality of life refers to the subjective assessment of patients regarding the physical, mental and social dimensions of well-being. Improving the quality of life of pregnant women requires better identification of their difficulties and guidance which offers assistance whenever possible.

[The "Wellbeing" project: To more reliably identify and support pregnant women with psychological or social vulnerabilities]. / Projet Bien-être : vers un meilleur repérage et accompagnement des femmes présentant des vulnérabilités psychologiques ou sociales.

The perinatal period is one of the most critical periods in the life cycle. The health of the mother and child are strongly and permanently influenced by events occurring during pregnancy, delivery or early infancy. In psychological terms, nearly 10% of women reported poor self-rated mental health during pregnancy. Moreover, sociodemographic characteristics indicative of social disadvantage are associated with a higher risk of poor self-rated mental health. 81.3% of these women did not consult a healthcare professional for psychological problems. The well-being project is designed to optimise the care of pregnant women with psychological or socioeconomic vulnerabilities and to assess the value of an early prenatal interview.

Intrinsic capacity and frailty in older adults with end-stage kidney disease undergoing pre-kidney transplant comprehensive geriatric assessment.

OBJECTIVE: Frailty has been extensively studied in end-stage kidney disease (ESKD) and kidney transplant (KT) patients. The identification of frailty is useful to predict adverse outcomes among ESKD and KT patients. The recent concept of intrinsic capacity (IC) appears as a good and easy-to-understand tool to screen for and monitor frailty in older adults with ESKD. This study aims to assess the relationships between frailty and IC in older adults with ESKD awaiting KT. DESIGN: Cross-sectional study SETTING AND PARTICIPANTS: 236 patients from a day-care geriatric unit undergoing pre-KT geriatric assessment between 2017 and 2022 were included in the main sample, and 151 patients in an independent multicentric replication sample. MEASUREMENTS: Frailty was evaluated using the physical frailty phenotype (PFP) and IC measures using the World Health Organization's screening (step 1) and diagnostic (step 2) tools for five IC domains (vitality, locomotion, audition, cognition, psychology). Multivariate regressions were run to assess relationships between PFP and IC domains, adjusted for age, sex, and comorbidities. Analyses were replicated using another independent multicenter cohort including 151 patients with ESKD to confirm the results. RESULTS: Impairments in the locomotion, psychology, and vitality IC domains according to WHO screening tools were associated with frailty (odds ratio 9.62 [95% CI 4.09-24.99], 3.19 [95% CI 1.11-8.88], and 3.11 [95% CI 1.32-7.29], respectively). When IC were measured linearly with z-scores, all IC domains except hearing were inversely associated with frailty. In the replication cohort, results were overall similar, with a greater association between psychology domain and frailty. CONCLUSION: This study highlights the relationship between frailty and IC in ESKD patients. We assume that IC may be assessed and monitored in ESKD patients, to predict and prevent future frailty, and post-KT adverse outcomes.

Endogenous GLP-1 levels play an important role in determining the efficacy of DPP-IV Inhibitors in both prediabetes and type 2 diabetes.

Background: In contrast to Western population, glucagon-like peptide-1 (GLP-1) levels are preserved in some East Asian population with type 2 diabetes (T2D), explaining why dipeptidyl peptidase-IV (DPP-IV) inhibitors are more effective in East Asians. We assessed whether differences in endogenous GLP-1 levels resulted in different treatment responses to DPP-IV inhibitors in prediabetes and T2D. Methods: A prospective 12-week study using linagliptin 5mg once daily in 50 subjects (28 prediabetes and 22 T2D) who were stratified into high versus low fasting GLP-1 groups. A 75-g oral glucose tolerance test (OGTT) was performed at week 0 and 12. Primary outcomes were changes in HbA1c, fasting and post-OGTT glucose after 12 weeks. Secondary outcomes included changes in insulin resistance and beta cell function indices. Results: There was a greater HbA1c reduction in subjects with high GLP-1 compared to low GLP-1 levels in both the prediabetes and T2D populations [least-squares mean (LS-mean) change of -0.33% vs. -0.11% and -1.48% vs. -0.90% respectively)]. Linagliptin significantly reduced glucose excursion by 18% in high GLP-1 compared with 8% in low GLP-1 prediabetes groups. The reduction in glucose excursion was greater in high GLP-1 compared to low GLP-1 T2D by 30% and 21% respectively. There were significant LS-mean between-group differences in fasting glucose (-0.95 mmol/L), 2-hour glucose post-OGTT (-2.4 mmol/L) in the high GLP-1 T2D group. Improvement in insulin resistance indices were seen in the high GLP-1 T2D group while high GLP-1 prediabetes group demonstrated improvement in beta cell function indices. No incidence of hypoglycemia was reported. Conclusions: Linagliptin resulted in a greater HbA1c reduction in the high GLP-1 prediabetes and T2D compared to low GLP-1 groups. Endogenous GLP-1 level play an important role in determining the efficacy of DPP-IV inhibitors irrespective of the abnormal glucose tolerance states.

Fasting and stimulated glucagon-like peptide-1 exhibit a compensatory adaptive response in diabetes and pre-diabetes states: A multi-ethnic comparative study.

Background: Impaired secretion of glucagon-like peptide-1 (GLP-1) among Caucasians contributes to reduced incretin effect in type 2 diabetes mellitus (T2DM) patients. However, studies emanating from East Asia suggested preserved GLP-1 levels in pre-diabetes (pre-DM) and T2DM. We aimed to resolve these conflicting findings by investigating GLP-1 levels during oral glucose tolerance test (OGTT) among Malay, Chinese, and Indian ethnicities with normal glucose tolerance (NGT), pre-DM, and T2DM. The association between total GLP-1 levels, insulin resistance, and insulin sensitivity, and GLP-1 predictors were also analyzed. Methods: A total of 174 subjects were divided into NGT (n=58), pre-DM (n=54), and T2DM (n=62). Plasma total GLP-1 concentrations were measured at 0, 30, and 120 min during a 75-g OGTT. Homeostasis model assessment of insulin resistance (HOMA-IR), HOMA of insulin sensitivity (HOMA-IS), and triglyceride-glucose index (TyG) were calculated. Results: Total GLP-1 levels at fasting and 30 min were significantly higher in T2DM compared with pre-DM and NGT (27.18 ± 11.56 pmol/L vs. 21.99 ± 10.16 pmol/L vs. 16.24 ± 7.79 pmol/L, p=0.001; and 50.22 ± 18.03 pmol/L vs. 41.05 ± 17.68 pmol/L vs. 31.44 ± 22.59 pmol/L, p<0.001; respectively). Ethnicity was a significant determinant of AUCGLP-1, with the Indians exhibiting higher GLP-1 responses than Chinese and Malays. Indians were the most insulin resistant, whereas Chinese were the most insulin sensitive. The GLP-1 levels were positively correlated with HOMA-IR and TyG but negatively correlated with HOMA-IS. This relationship was evident among Indians who exhibited augmented GLP-1 responses proportionately to their high insulin-resistant states. Conclusion: This is the first study that showed GLP-1 responses are augmented as IR states increase. Fasting and post-OGTT GLP-1 levels are raised in T2DM and pre-DM compared to that in NGT. This raises a possibility of an adaptive compensatory response that has not been reported before. Among the three ethnic groups, the Indians has the highest IR and GLP-1 levels supporting the notion of an adaptive compensatory secretion of GLP-1.

Plethora of Antibiotics Usage and Evaluation of Carbapenem Prescribing Pattern in Intensive Care Units: A Single-Center Experience of Malaysian Academic Hospital.

Excessive antibiotic consumption is still common among critically ill patients admitted to intensive care units (ICU), especially during the coronavirus disease 2019 (COVID-19) period. Moreover, information regarding antimicrobial consumption among ICUs in South-East Asia remains scarce and limited. This study aims to determine antibiotics utilization in ICUs by measuring antibiotics consumption over the past six years (2016−2021) and specifically evaluating carbapenems prescribed in a COVID-19 ICU and a general intensive care unit (GICU) during the second year of the COVID-19 pandemic. (2) Methods: This is a retrospective cross-sectional observational analysis of antibiotics consumption and carbapenems prescriptions. Antibiotic utilization data were estimated using the WHO Defined Daily Doses (DDD). Carbapenems prescription information was extracted from the audits conducted by ward pharmacists. Patients who were prescribed carbapenems during their admission to COVID-19 ICU and GICU were included. Patients who passed away before being reviewed by the pharmacists were excluded. (3) Results: In general, antibiotics consumption increased markedly in the year 2021 when compared to previous years. Majority of carbapenems were prescribed empirically (86.8%). Comparing COVID-19 ICU and GICU, the reasons for empirical carbapenems therapy in COVID-19 ICU was predominantly for therapy escalation (64.7% COVID-19 ICU vs. 34% GICU, p < 0.001), whereas empirical prescription in GICU was for coverage of extended-spectrum beta-lactamases (ESBL) gram-negative bacteria (GNB) (45.3% GICU vs. 22.4% COVID-19 ICU, p = 0.005). Despite microbiological evidence, the empirical carbapenems were continued for a median (interquartile range (IQR)) of seven (5−8) days. This implies the need for a rapid diagnostic assay on direct specimens, together with comprehensive antimicrobial stewardship (AMS) discourse with intensivists to address this issue.

Development and validation of Malaysia Medication Adherence Assessment Tool (MyMAAT) for diabetic patients.

Medication non-adherence remains a significant barrier in achieving better health outcomes for patients with chronic diseases. Previous self-reported medication adherence tools were not developed in the context of the Malaysia population. The most commonly used tool, MMAS-8, is no longer economical because it requires a license and currently every form used is charged. Hence, there is a need to develop and validate a new medication adherence tool. The Malaysia Medication Adherence Assessment Tool (MyMAAT) was developed by a multidisciplinary team with expertise in medication adherence and health literacy. The face and content validities of the MyMAAT was established by a panel of experts. A total of 495 patients with type 2 diabetes were recruited from the Ministry of Health facilities consisting of five hospitals and five primary health clinics. A test-retest was conducted on 42 of the patients one week following their first data collection. Exploratory factor analysis was performed to evaluate the validity of the MyMAAT. The final item for MyMAAT was compared with SEAMS, HbA1c%, Medication Possession ratio (MPR) score, and pharmacist's subjective assessment for its hypothesis testing validity. The MyMAAT-12 achieved acceptable internal consistency (Cronbach's alpha = 0.910) and stable reliability as the test-retest score showed good to excellent correlation (Spearman's rho = 0.96, p = 0.001). The MyMAAT has significant moderate association with SEAMS (Spearman's rho = 0.44, p = < 0.001) and significant relationship with HbA1c (< 8% and ≥ 8%) (χ2(1) = 13.4, p < 0.001), MPR (χ2(1) = 13.6, p < 0.001) and pharmacist's subjective assessment categories (χ2(1) = 31, p < 0.001). The sensitivity of MyMAAT-12, tested against HbA1c% was 72.9% while its specificity was 43%. This study demonstrates that the MyMAAT-12 together with other methods of assessment may make a better screening tool to identify patients who were non-adherence to their medications.

Effects of a systematically offered social and preventive medicine consultation on training and health attitudes of young people not in employment, education or training (NEETs): An interventional study in France.

BACKGROUND: NEETs (young people not in employment, education or training) are at higher risk for poorer mental and physical health. In France, the Missions locales (MLs) are the only social structures dedicated to this population. We sought to determine whether the systematic offer of a social and preventive medicine consultation at a ML might increase NEET participants' access to training in the 12 months following the intervention. METHODS: This intervention research was a parallel randomised controlled interventional study conducted at five MLs in mainland France in 2011-2012. It included 976 NEETs aged 18 to 25 years who attended one of the five MLs. At inclusion, participants were randomly assigned (1:1:1) to three groups: those in the first group were invited to see a social worker (not studied in this paper), those in the second group were invited to see a doctor and a social worker (intervention group), and the third was a control group. The primary outcome was participation in at least one training session during the year following study inclusion. RESULTS: Among the 976 participants, 504 were randomly assigned to the intervention group and 472 to the control group; 704 (72.1%) were included in the analyses. A significantly higher proportion of the participants in the intervention group participated in a training session in the 12 months following the intervention than of those in the control group (63.3% vs 55.6%; p = 0.04). This difference was significantly greater for women, those less than 21 years of age, those unstably housed and those with a lower level of education. CONCLUSIONS: Social and preventive medicine consultations that are fully integrated into the social services for NEETs have an impact on their access to training and contribute to changing some of their health-related behaviours. This may improve their access to the labour market.

Social inequalities in health and mental health in France. The results of a 2010 population-based survey in Paris Metropolitan Area.

The present study aimed to assess socioeconomic inequalities in general and mental health, depression and substance use disorders (daily tobacco use, hazardous alcohol use). Data from the 2010 SIRS (French acronym for Health, Inequalities, and Social Ruptures) study, which is deemed to be representative of the French-speaking adult population living in the Paris Metropolitan Area, were analysed. Different socioeconomic position indicators were selected: education, income and perceived financial status. Absolute measures (the slope index of inequality (SII)) and relative measures (the odds ratio (OR) and relative index of inequality (RII)) of health inequalities were used. The OR, RII and SII were adjusted for age, household type and migration characteristics and all analyses were performed separately for men and women. The study included 3,006 adults. The results showed significant relative and absolute socioeconomic inequalities in general, mental health and depression for all socioeconomic position indicators considered (education, income, and perceived financial status). The absolute inequalities were greater for women than for men. Strongest inequalities were observed by perceived financial status for men and women. Education seemed to play a stronger role in inequalities for women, whereas, for men, income seemed to play a stronger role. Only few socioeconomic inequalities were found in daily tobacco use, while a reversed gradient was observed for hazardous alcohol use. We hope that these results will be regularly re-evaluated and compared across time in order to monitor socioeconomic inequalities in health.

Non-invasive CT screening for pulmonary arteriovenous malformations in children with confirmed hereditary hemorrhagic telangiectasia: Results from two pediatric centers.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that is caused by mutations in mainly two genes, that is ENG, encoding endoglin (HHT1), or ACVRL1, encoding activin receptor-like kinase 1 (ALK-1/HHT2). HHT is characterized by recurrent epistaxis, mucocutaneous telangiectasia, and vascular visceral dysplasia responsible for visceral arteriovenous malformations (AVM). AIM: to report the experience of two university hospitals (Trousseau, Paris, and CHIC, Creteil) with screening children for HHT and pulmonary AVM (PAVM) using high resolution computed tomography (HRCT). METHODS: parents with confirmed HHT were offered to have their children screened for the mutation identified in their family, and informed consent was obtained. Children carrying the same mutation as their parents underwent HRCT of the chest without contrast. RESULTS: between 2008 and 2015, 99 children were screened for HHT mutations. Mutations were identified in 59 patients, that is 24 HHT1 and 35 HHT2. Radiologic and clinical screening was possible in 52 patients (21 HHT-1 and 31 HHT-2). Among those, PAVM was identified in 13 patients (25%; n = 8 HHT1; n = 5 HHT2), and four of them required embolization therapy. CONCLUSION: This study highlights the usefulness of genetic screening in children with known HHT family. It also suggests that a non-invasive protocol such as HRTC is an efficient approach to detect non-symptomatic lesions that are present early on in children carrying the ENG (HHT1), but also the ACVRL1 mutations (HHT2). Pediatr Pulmonol. 2017;52:642-649. © 2017 Wiley Periodicals, Inc.

Improvement in binge eating in non-diabetic obese individuals after 3 months of treatment with liraglutide - A pilot study.

We examined the effects of liraglutide, a glucagon-like peptide-1 analogue on appetite and plasma ghrelin in non-diabetic obese participants with subclinical binge eating (BE). Forty-four obese BE participants (mean age: 34±9 years, BMI: 35.9±4.2kg/m(2)) were randomly assigned to intervention or control groups for 12 weeks. All participants received standard advice for diet and exercise. Binge eating score, ghrelin levels and other anthropometric variables were evaluated at baseline and at the end of the study. Participants who received liraglutide showed significant improvement in binge eating, accompanied by reduction in body weight, BMI, waist circumference, systolic blood pressure, fasting glucose and total cholesterol. Ghrelin levels were significantly increased which may potentially diminish the weight loss effects of liraglutide beyond the intervention.

Correction: Postnatal Environmental Tobacco Smoke Exposure Related to Behavioral Problems in Children.

[This corrects the article DOI: 10.1371/journal.pone.0133604.].

Postnatal Environmental Tobacco Smoke Exposure Related to Behavioral Problems in Children.

OBJECTIVE: The purpose of this study was to examine the association between pre and post environmental tobacco smoke (ETS) exposure and behavioral problems in schoolchildren. METHODS: In the cross-sectional 6 cities Study conducted in France, 5221 primary school children were investigated. Pre- and postnatal exposure to secondhand tobacco smoke at home was assessed using a parent questionnaire. Child's behavioral outcomes (emotional symptoms and conduct problems) were evaluated by the Strengths and Difficulties Questionnaire (SDQ) completed by the parents. RESULTS: ETS exposure during the postnatal period and during both pre- and postnatal periods was associated with behavioral problems in children. Abnormal emotional symptoms (internalizing problems) were related to ETS exposure in children who were exposed during the pre- and postnatal periods with an OR of 1.72 (95% Confidence Interval (CI)= 1.36-2.17), whereas the OR was estimated to be 1.38 (95% CI= 1.12-1.69) in the case of postnatal exposure only. Abnormal conduct problems (externalizing problems) were related to ETS exposure in children who were exposed during the pre- and postnatal periods with an OR of 1.94 (95% CI= 1.51-2.50), whereas the OR was estimated to be 1.47 (95% CI=1.17-1.84) in the case of postnatal exposure only. Effect estimates were adjusted for gender, study center, ethnic origin, child age, low parental education, current physician diagnosed asthma, siblings, preterm birth and single parenthood. CONCLUSION: Postnatal ETS exposure, alone or in association with prenatal exposure, increases the risk of behavioral problems in school-age children.

The validation of the malay version of binge eating scale: a comparison with the structured clinical interview for the DSM-IV.

BACKGROUND: The Binge Eating Scale (BES) questionnaire is a self-administered instrument developed to identify binge eaters. The aim of this study was to assess the validity of the Malay language version of BES as a screening instrument for binge eating. A cut-off point of 17 is taken as comparable to the Structured Clinical Interview for the DSM-IV patient version (SCID-I/P), the gold standard for the diagnosis of Binge Eating Disorder. METHOD: The questionnaire was structured from the English version of the original scale which has 16 items. The sample was obtained from outpatients and healthy adult volunteers at a teaching hospital. After completion of BES, the participants were interviewed with the SCID-I/P. The interviewer was blinded to the BES score. RESULTS: The Malay version of BES yielded a sensitivity of 84.6%, specificity of 94.9%, a positive predictive value of 81.8%, a negative predictive value of 95.7%. Area under the curve was 0.95 (95% confidence interval: 0.90-0.99). The results of factor analysis indicated a two factor structure of feelings/cognition and behavioural manifestation of binge eating. Internal consistency, Cronbach's alpha was 0.89. CONCLUSION: The BES performed satisfactorily as a valid instrument for screening of binge eating among Malay-speaking population.