Antibiotic use in pre-school children and the correlation with adult educational levels in two Nordic counties: a replication of a 20-year-old study.

OBJECTIVE: The aim of this study was to describe the change of antibiotic prescribing in pre-school children in the municipalities of the former Copenhagen County in Denmark and Skåne County in Sweden after 20 years of antibiotic stewardship effort. Furthermore, the variation in the prescribing of antibiotics between the municipalities and the correlation between municipal adult educational level and antibiotic prescribing in pre-school children was assessed. METHODS: In this ecological study, information on antibiotic prescribing in pre-school children was obtained from a central pharmacy settlement system in each Region. The antibiotic prescribing rate was expressed in defined daily doses per 1,000 inhabitants per day (DDD/TID) and number of prescriptions/1000 inhabitants. Information on municipal adult educational levels was obtained from Statistics Denmark and Statistics Sweden. RESULTS: The antibiotic prescribing rate during 2017 was higher in the municipalities of Copenhagen County (5.6-7.9 DDD/TID) compared to the municipalities of Skåne County (4.2-6.6 DDD/TID). In 1998 a higher rate was found in Skåne County (9.6-17.7 DDD/TID) compared to Copenhagen County (8.0-12.9 DDD/TID). A non-significant negative correlation between adult educational levels and antibiotic prescribing was observed in the municipalities of Copenhagen County (r= -0.233, p = .352) while the correlation was positive in the municipalities of Skåne County (r= +0.410, p = .018). The same correlations were observed in 1998. CONCLUSION: We found higher antibiotic prescribing in pre-school children in the municipalities of Copenhagen County compared to Skåne County in 2017, suggesting a possible overuse of antibiotics in Denmark. Further research should try to elucidate the reasons for the observed variation.

Antibiotic-prescribing and antibiotic-resistance patterns among elderly citizens residing in two Nordic regions.

Objective: The objective of this study was to compare antibiotic-prescribing rates in 2016 and antibiotic-resistance rates in 2017 among citizens aged ≥85 years between the Capital Region in Denmark and the Skåne Region in Sweden, with regards to overall antibiotic use and antibiotics of choice for urinary tract infections (UTIs) and skin and soft tissue infections (SSTIs). Methods: Inhabitants ≥85 year old on the date of prescription during 2016 and residing in the Capital Region or the Skåne Region were included for antibiotic-prescription analyses. Samples from 2017 from residents of the same regions who were ≥85 years old were included for antibiotic-resistance analyses. Antimicrobial use was determined according to the drugs of choice for UTIs and SSTIs in Denmark and Sweden. Students t-tests were used to compare antibiotic prescribing while a Chi-Squared test was performed to compare antibiotic resistance. Results: There was a significantly higher overall prescription rate among citizens ≥85 years in the Capital Region than in the Skåne Region. The same pattern was evident for the antibiotics of choice for UTIs and SSTIs except for clindamycin. Antibiotic resistance against all antibiotics included was more prominent in the Capital Region than in the Skåne Region. Conclusion: Considerable variation in antibiotic prescribing and resistance exists among elderly citizens between these two adjacent Nordic regions. Information and reflection on current practices and resistance patterns may direct attention towards antimicrobial stewardship as a higher priority and may help inform and motivate prescribing behaviours.

Incidence Rates of Treated Mental Disorders in Childhood and Adolescence in a Complete Nationwide Birth Cohort.

OBJECTIVE: To investigate incidences, cumulative incidence rates, and risk factors of diagnosed mental disorders in a complete nationwide birth cohort across the entire period of childhood and adolescence. METHODS: Based on nationwide Danish registries, the entire cohort of all children born in 1995 was followed up to December 31, 2013. Data for children who migrated during the period were censored in the time analyses, and death before age 18 years was considered a competing risk. Incidence rates and cumulative incidence rates for any first-time-diagnosed mental disorder and 10 major categories of mental disorders according to ICD-10 criteria were calculated for 68,982 individuals. In addition, the effects of age, sex, and further child- and family-related risk factors on mental disorders were analyzed. RESULTS: The incidences of any mental disorder, substance use disorders, depression, and anxiety disorders showed an increase in adolescence, whereas those for autism spectrum disorders, attention-deficit/hyperactivity disorder, conduct disorder, and tic disorder increased during childhood and decreased thereafter. Males had higher incidence rates of any mental disorders, substance use disorders, autism spectrum disorders, ADHD, conduct disorder, and tic disorder. Females had higher risks for depressive, anxiety, obsessive-compulsive, and eating disorders. Several other risk and protective factors for any mental disorder were identified. The cumulative incidence rate at age 18 years amounted to 11.02% for any mental disorder. CONCLUSIONS: These findings provide the most comprehensive estimates of the development, incidence rates, and contributing risk factors of registered mental disorders for the entire period of childhood and adolescence that have been calculated so far.

Characteristics of Young Adults with Autism Spectrum Disorder Performing Different Daytime Activities.

Daytime activity, in terms of engagement in an occupation or education, is highly important for individuals with autism spectrum disorder (ASD), regardless of their level of functioning. In this nationwide survey, the parents of young adults diagnosed with ASD in childhood (n = 1266) provided information about the current daytime activity of their child, as well as behavioral characteristics, comorbidity, history of schooling during primary and secondary school, and availability of support. The young adults without a regular daytime activity constituted approximately one-fifth of the sample and had more behavioral difficulties and comorbidities than young adults with a daytime activity. Intellectual disability, part-time job, history of schooling, including type of school, and availability of support were found to be associated with daytime activity.

Quality of life in adolescents and adults with autism spectrum disorder: Results from a nationwide Danish survey using self-reports and parental proxy-reports.

BACKGROUND: Quality of life (QoL) in individuals with autism spectrum disorder (ASD) is essential to investigate with regard to knowledge about factors of importance for QoL and concordance between self-reported and parental proxy-reported QoL. AIMS: This study investigated QoL in adolescents and adults with ASD using both self-reports and parental proxy-reports. METHODS: From a nationwide survey, 1738 individuals diagnosed with ASD in childhood, were included for this study. The individuals themselves and/or their parents completed the INICO-FEAPS scale. Concordance between self-reports and proxy-reports were examined, and factors associated with QoL were explored via linear regression models. RESULTS: Compared to proxy-reported QoL scores, self-reported QoL scores were significantly but only slightly higher and not in every QoL domain. Independent of respondent type it was found that psychiatric comorbidity, sleeping difficulty, intellectual disability, maladaptive behavior, adaptive functioning, autism symptomatology, main daytime activity and residence were associated with QoL. CONCLUSION: Proxy-reported QoL is different from self-reported QoL and should be considered as an alternative source of information. QoL might be enhanced when factors associated with QoL are improved. However, large variations in QoL were found for most factors, suggesting the need to involve the individuals with ASD and/or their families when improving their QoL.

Psychometric properties of the INICO-FEAPS scale in a Danish sample with autism spectrum disorders.

BACKGROUND: There is a need to evaluate subjective perspectives of outcomes, such as quality of life (QoL), in individuals with autism spectrum disorders (ASD), but to date, there is no specific instrument available to assess this population. While the INICO-FEAPS scale is customized for studying QoL in adolescents and adults with intellectual and/or developmental disabilities, this scale has not been previously evaluated in an ASD population. AIMS: To examine the usability of the INICO-FEAPS scale in a Danish population of adolescents and adults with ASD. METHODS: In a nationwide survey, 875 adolescents and adults with ASD and 1573 parents completed the INICO-FEAPS scale. Internal consistency was evaluated through several indices. Confirmatory factor analysis (CFA) was conducted to investigate the fit of the model with eight correlated first-order factors, and convergent validity was explored comparing the results of different QoL measures through correlation analysis. RESULTS: Internal consistency was adequate for the indices applied, and the CFA model tested indicated an acceptable fit to the data. Generally, comparisons of results of different QoL measures resulted in moderate to high correlations. CONCLUSION: Overall, it was concluded that due to the psychometric properties found, the INICO-FEAPS scale is applicable for use in ASD populations.

Family aggregation and risk factors in substance use disorders over three generations in a nation-wide study.

OBJECTIVE: This nation-wide register-based study investigated how often substance use disorders (SUD) and co-morbid disorders occurred in affected families compared to control families. METHOD: A total of N = 2504 child and adolescent psychiatric participants who were born between 1969 and 1986 and were registered in the Danish Psychiatric Central Research Register (DPCRR) had a mental disorder before the age of 18 and developed SUD at some point during their life-time. In addition, N = 7472 controls without any psychiatric diagnosis before age 18 and matched for age, sex, and residential region were included. Psychiatric diagnoses of the first-degree relatives were also obtained. A family load component was assessed. RESULTS: SUD occurred significantly more often in case families than in control families. SUD risk factors included SUD, depression, anxiety disorders, personality disorders, or conduct disorders in the family. Furthermore, male sex, more recent year of birth, and living in the capital city of Copenhagen were also significantly associated with having SUD. The family load explained 30% of the SUD manifestation in the case-probands. The findings in the total SUD group were mostly replicated in the two major subgroups of pure alcohol or multiple substance use disorders. DISCUSSION: These findings based on a very large and representative dataset provide additional evidence for the strong family aggregation and further risk factors in SUD. The pattern of risk factors is largely the same for the total group of SUD and the major subgroups of pure alcohol and multiple substance use disorders.

Effective Mental Health Screening in Adolescents: Should We Collect Data from Youth, Parents or Both?

Youth- and parent-rated screening measures derived from the Strengths and Difficulties Questionnaire (SDQ) and Development and Well-Being Assessment (DAWBA) were compared on their psychometric properties as predictors of caseness in adolescence (mean age 14). Successful screening was judged firstly against the likelihood of having an ICD-10 psychiatric diagnosis and secondly by the ability to discriminate between community (N = 252) and clinical (N = 86) samples (sample status). Both, SDQ and DAWBA measures adequately predicted the presence of an ICD-10 disorder as well as sample status. The hypothesis that there was an informant gradient was confirmed: youth self-reports were less discriminating than parent reports, whereas combined parent and youth reports were more discriminating-a finding replicated across a diversity of measures. When practical constraints only permit screening for caseness using either a parent or an adolescent informant, parents are the better source of information.

Family Aggregation and Risk Factors in Phobic Disorders over Three-Generations in a Nation-Wide Study.

OBJECTIVE: This nation-wide register-based study investigated how often phobic disorders (PHO) and co-morbid disorders occur in affected families compared to control families. Furthermore, the study addressed the impact of sex, year of birth, and degree of urbanization in terms of risk factors. METHOD: A total of N = 746 child and adolescent psychiatric participants born between 1969 and 1986 and registered in the Danish Psychiatric Central Research Register (DPCRR) with a diagnosis of a mental disorder before the age of 18, and developed PHO at some point during their life-time until a maximum age of 40 years were included. In addition, N = 2229 controls without any diagnosis of mental disorders before age 18 and that were matched for age, sex, and residential region were included. Diagnoses of mental disorders were also obtained from the first- degree relatives as a part of the Danish Three Generation Study (3GS). A family load component was obtained by using various mixed regression models. RESULTS: PHO occurred significantly more often in case than in control families, in particular, in mothers and siblings. Substance use disorders (SUD), Depressive disorders (DEP), anxiety disorders (ANX) and personality disorders (PERS) in the family were significantly associated with specific phobia in the case-probands. After controlling for various mental disorders comorbid to PHO it was found that some of the family transmission could be caused by various other mental disorders in family members rather than the PHO itself. Female sex and more recent year of birth were further risk factors while region of residence was not related to the manifestation of PHO. Case-relatives did not develop PHO earlier than control relatives. After adjusting for various additional explanatory variables, the family load explained only 0.0013% of the variance in the manifestation of PHO in the case-probands. DISCUSSION: These findings, based on a very large and representative dataset, provide evidence for the family aggregation and further risk factors in PHO. In contrast to anxiety disorders and other major mental disorders the family load of PHO in this nation-wide study was rather low.

[Ca2+]i Oscillations and IL-6 Release Induced by α-Hemolysin from Escherichia coli Require P2 Receptor Activation in Renal Epithelia.

Urinary tract infections are commonly caused by α-hemolysin (HlyA)-producing Escherichia coli. In erythrocytes, the cytotoxic effect of HlyA is strongly amplified by P2X receptors, which are activated by extracellular ATP released from the cytosol of the erythrocytes. In renal epithelia, HlyA causes reversible [Ca(2+)]i oscillations, which trigger interleukin-6 (IL-6) and IL-8 release. We speculate that this effect is caused by HlyA-induced ATP release from the epithelial cells and successive P2 receptor activation. Here, we demonstrate that HlyA-induced [Ca(2+)]i oscillations in renal epithelia were completely prevented by scavenging extracellular ATP. In accordance, HlyA was unable to inflict any [Ca(2+)]i oscillations in 132-1N1 cells, which lack P2R completely. After transfecting these cells with the hP2Y2 receptor, HlyA readily triggered [Ca(2+)]i oscillations, which were abolished by P2 receptor antagonists. Moreover, HlyA-induced [Ca(2+)]i oscillations were markedly reduced in medullary thick ascending limbs isolated from P2Y2 receptor-deficient mice compared with wild type. Interestingly, the following HlyA-induced IL-6 release was absent in P2Y2 receptor-deficient mice. This suggests that HlyA induces ATP release from renal epithelia, which via P2Y2 receptors is the main mediator of HlyA-induced [Ca(2+)]i oscillations and IL-6 release. This supports the notion that ATP signaling occurs early during bacterial infection and is a key player in the further inflammatory response.

A nation-wide study of the family aggregation and risk factors in anorexia nervosa over three generations.

OBJECTIVE: This nation-wide register-based study investigated how often anorexia nervosa (AN) and co-morbid disorders occur in affected families compared with control families. Furthermore, the study addressed the impact of sex, year of birth, and degree of urbanization in terms of risk factors. METHOD: A total of N = 2,370 child and adolescent psychiatric subjects born between 1951 and 1996 and registered in the Danish Psychiatric Central Research Register (DPCRR) had any mental disorder before the age of 18 and developed AN at some point during their life-time. In addition, N = 7,035 controls without any psychiatric diagnosis before age 18 and matched for age, sex, and residential region were included. Psychiatric diagnoses were also obtained on the first-degree relatives as a part of the Danish Three Generation Study (3GS). A family load component was obtained by using various mixed regression models. RESULTS: AN occurred significantly more often in case than in control families. AN Risk factors included having a sibling with AN, affective disorders in family members, and co-morbid affective, anxiety, obsessive-compulsive, personality, or substance use disorders. Furthermore, female sex, and ascending year of birth were significantly associated with having AN. Urbanization was not related to the family load of AN and case-relatives did not develop AN earlier than control relatives. DISCUSSION: These findings based on a very large and representative dataset provide evidence for the family aggregation and further risk factors in AN.

Risk of diabetes in children and adolescents exposed to antipsychotics: a nationwide 12-year case-control study.

OBJECTIVE: Antipsychotics are associated with weight gain and diabetes. The risk and rate of diabetes in children and adolescents treated with antipsychotics is unclear. METHOD: A longitudinal register linkage case-control study of diabetes in all psychiatric patients aged <18 years in Denmark was performed from January 1999 through the end of June 2010. Patients with and without antipsychotic exposure were compared regarding the occurrence of type 2 diabetes, defined as the prescription of oral antidiabetic medication. Regression analyses with type 2 diabetes as the dependent variable were conducted with sex, age, and diagnoses as covariates. RESULTS: We compared the risk of diabetes in 48,299 psychiatrically ill youth. Of 7,253 youth exposed to antipsychotics, 52 (0.72%; 95% CI = 0.52% - 0.91%) developed type 2 diabetes. Of 41,046 youth without exposure to antipsychotics, 111 (0.27%; 95% CI = 0.22% - 0.32%) developed type 2 diabetes. In a 25,033 + 16,013 logistic regression analysis, type 2 diabetes development was associated with antipsychotic drug exposure (odds ratio [OR] = 1.60; 95% CI = 1.08 - 2.36, p < .05) female sex, (OR = 4.48; 95% CI = 2.90 - 6.91, p < 0.001) and older age at first psychiatric diagnosis (OR = 1.19; 95% CI = 1.12 - 1.27, p < 0.001), but not with psychiatric diagnosis. In a Cox-regression analysis, shorter time to type 2 diabetes onset was associated with female sex (Hazard Ratio (HR) = 4.83; 95% CI = 3.05-7.66, p = 0.001), and older age at first psychiatric diagnosis (HR = 1.19; 95% CI = 1.12-1.28, p = 0.001), while antipsychotic exposure (HR) = 1.41; 95% CI = 0.92-2.16, p = 0.11) trended towards increasing the rate of diabetes. CONCLUSION: Antipsychotic treatment, female sex, and older age at psychiatric diagnosis were associated with a significantly more frequent type 2 diabetes onset in children and adolescents. Strict indications for antipsychotic treatment and routine cardiometabolic monitoring are crucial.

Loss of NDG-4 extends lifespan and stress resistance in Caenorhabditis elegans.

NDG-4 is a predicted transmembrane acyltransferase protein that acts in the distribution of lipophilic factors. Consequently, ndg-4 mutants lay eggs with a pale appearance due to lack of yolk, and they are resistant to sterility caused by dietary supplementation with the long-chain omega-6 polyunsaturated fatty acid dihommogamma-linolenic acid (DGLA). Two other proteins, NRF-5 and NRF-6, a homolog of a mammalian secreted lipid binding protein and a NDG-4 homolog, respectively, have previously been shown to function in the same lipid transport pathway. Here, we report that mutation of the NDG-4 protein results in increased organismal stress resistance and lifespan. When NDG-4 function and insulin/IGF-1 signaling are reduced simultaneously, maximum lifespan is increased almost fivefold. Thus, longevity conferred by mutation of ndg-4 is partially overlapping with insulin signaling. The nuclear hormone receptor NHR-80 (HNF4 homolog) is required for longevity in germline less animals. We find that NHR-80 is also required for longevity of ndg-4 mutants. Moreover, we find that nrf-5 and nrf-6 mutants also have extended lifespan and increased stress resistance, suggesting that altered lipid transport and metabolism play key roles in determining lifespan.

A new role for laminins as modulators of protein toxicity in Caenorhabditis elegans.

Protein misfolding is a common theme in aging and several age-related diseases such as Alzheimer's and Parkinson's disease. The processes involved in the development of these diseases are many and complex. Here, we show that components of the basement membrane (BM), particularly laminin, affect protein integrity of the muscle cells they support. We knocked down gene expression of epi-1, a laminin α-chain, and found that this resulted in increased proteotoxicity in different Caenorhabditis elegans transgenic models, expressing aggregating proteins in the body wall muscle. The effect could partially be rescued by decreased insulin-like signaling, known to slow the aging process and the onset of various age-related diseases. Our data points to an underlying molecular mechanism involving proteasomal degradation and HSP-16 chaperone activity. Furthermore, epi-1-depleted animals had altered synaptic function and displayed hypersensitivity to both levamisole and aldicarb, an acetylcholine receptor agonist and an acetylcholinesterase inhibitor, respectively. Our results implicate the BM as an extracellular modulator of protein homeostasis in the adjacent muscle cells. This is in agreement with previous research showing that imbalance in neuromuscular signaling disturbs protein homeostasis in the postsynaptic cell. In our study, proteotoxicity may indeed be mediated by the neuromuscular junction which is part of the BM, where laminins are present in high concentration, ensuring the proper microenvironment for neuromuscular signaling. Laminins are evolutionarily conserved, and thus the BM may play a much more causal role in protein misfolding diseases than currently recognized.

Comprehensive discharge follow-up in patients' homes by GPs and district nurses of elderly patients. A randomized controlled trial.

OBJECTIVES: Many hospital admissions are due to inappropriate medical treatment, and discharge of fragile elderly patients involves a high risk of readmission. The present study aimed to assess whether a follow-up programme undertaken by GPs and district nurses could improve the quality of the medical treatment and reduce the risk of readmission of elderly newly discharged patients. DESIGN AND SETTING: The patients were randomized to either an intervention group receiving a structured home visit by the GP and the district nurse one week after discharge followed by two contacts after three and eight weeks, or to a control group receiving the usual care. PATIENTS: A total of 331 patients aged 78+ years discharged from Glostrup Hospital, Denmark, were included. MAIN OUTCOME MEASURES: Readmission rate within 26 weeks after discharge among all randomized patients. Control of medication, evaluated 12 weeks after discharge on 293 (89%) of the patients by an interview at home and by a questionnaire to the GP. RESULTS: Control-group patients were more likely to be readmitted than intervention-group patients (52% v 40%; p = 0.03). In the intervention group, the proportions of patients who used prescribed medication of which the GP was unaware (48% vs. 34%; p = 0.02) and who did not take the medication prescribed by the GP (39% vs. 28%; p = 0.05) were smaller than in the control group. CONCLUSION: The intervention shows a possible framework securing the follow-up on elderly patients after discharge by reducing the readmission risk and improving medication control.

Deconstructing PTI-1: PTI-1 is a truncated, but not mutated, form of translation elongatin factor 1A1, eEF1A1.

The prostate tumor-inducing gene 1 (PTI-1) transcript is detected in various human carcinoma cells. PTI-1 is reported to consist of a 5' untranslated region (5' UTR) homologous to mycoplasma 23S rRNA and a coding region corresponding to a truncated and mutated form of the translation elongation factor 1A, eEF1A. We have found that the PTI-1 transcript may encode a truncated, but not mutated, form of the human isoform eEF1A1. Additionally, the 5' UTR sequence of PTI-1 from genomic DNA of different cell lines and blood samples varies from the original sequence. This 5' -UTR region of PTI-1 presents a fusion of E. coli and Mycoplasma hyorhinis 23S rRNA. We have overexpressed the potential PTI-1 protein in E. coli and various human cell lines. The resulting protein could be detected by western blotting using anti-eEF1A antibodies. However, we were unable to detect the PTI-1 protein in LNCaP cell extracts. The potential roles of the PTI-1 protein in carcinogenesis and the origin of the PTI-1 gene in the human genome are discussed.