Epigenetic Alterations in Liver of C57BL/6J Mice after Short-Term Inhalational Exposure to 1,3-Butadiene

Background1,3-Butadiene (BD) is a high-volume industrial chemical and a known human carcinogen. The main mode of BD carcinogenicity is thought to involve formation of genotoxic epoxides.ObjectivesIn this study we tested the hypothesis that BD may be epigenotoxic (i.e., cause changes in DNA and histone methylation) and explored the possible molecular mechanisms for the epigenetic changes.Methods and ResultsWe administered BD (6.25 and 625 ppm) to C57BL/6J male mice by inhalation for 2 weeks (6 hr/day, 5 days a week) and then examined liver tissue from these mice for signs of toxicity using histopathology and gene expression analyses. We observed no changes in mice exposed to 6.25 ppm BD, but glycogen depletion and dysregulation of hepatotoxicity biomarker genes were observed in mice exposed to 625 ppm BD. We detected N-7-(2,3,4-trihydroxybut-1-yl)guanine (THB-Gua) adducts in liver DNA of exposed mice in a dose-responsive manner, and also observed extensive alterations in the cellular epigenome in the liver, including demethylation of global DNA and repetitive elements and a decrease in histone H3 and H4 lysine methylation. In addition, we observed down-regulation of DNA methyltransferase 1 (Dnmt1) and suppressor of variegation 3–9 homolog 1, a histone lysine methyltransferase (Suv39h1), and up-regulation of the histone demethylase Jumonji domain 2 (Jmjd2a), proteins responsible for the accurate maintenance of the epigenetic marks. Although the epigenetic effects were most pronounced in the 625-ppm exposure group, some effects were evident in mice exposed to 6.25 ppm BD.ConclusionsThis study demonstrates that exposure to BD leads to epigenetic alterations in the liver, which may be important contributors to the mode of BD carcinogenicity

Health care restructuring and family physician care for those who died of cancer

BACKGROUND: During the 1990s, health care restructuring in Nova Scotia resulted in downsized hospitals, reduced inpatient length of stay, capped physician incomes and restricted practice locations. Concurrently, the provincial homecare program was redeveloped and out-of-hospital cancer deaths increased from 20% (1992) to 30% (1998). These factors all pointed to a transfer of end-of-life inpatient hospital care to more community-based care. The purpose of this study was to describe the trends in the provision of Family Physician (FP) visits to advanced cancer patients in Nova Scotia (NS) during the years of health care restructuring. METHODS: Design Secondary multivariate analysis of linked population-based datafiles including the Queen Elizabeth II Health Sciences Centre Oncology Patient Information System (NS Cancer Registry, Vital Statistics), the NS Hospital Admissions/Separations file and the Medical Services Insurance Physician Services database. Setting Nova Scotia, an eastern Canadian province (population: 950,000). Subjects: All patients who died of lung, colorectal, breast or prostate cancer between April 1992 and March 1998 (N = 7,212). Outcome Measures Inpatient and ambulatory FP visits, ambulatory visits by location (office, home, long-term care facility, emergency department), time of day (regular hours, after hours), total length of inpatient hospital stay and number of hospital admissions during the last six months of life. RESULTS: In total, 139,641 visits were provided by family physicians: 15% of visits in the office, 10% in the home, 5% in the emergency department (ED), 5% in a long-term-care centre and 64% to hospital inpatients. There was no change in the rate of FP visits received for office, home and long-term care despite the fact that there were 13% fewer hospital admissions, and length of hospital stay declined by 21%. Age-sex adjusted estimates using negative binomial regression indicate a decline in hospital inpatient FP visits over time compared to 1992–93 levels (for 1997–98, adjusted RR = 0.88, 95%CI = 0.81–0.95) and an increase in FP ED visits (for 1997–98, adjusted RR = 1.18, 95%CI = 1.05–1.34). CONCLUSION: Despite hospital downsizing and fewer deaths occurring in hospitals, FP ambulatory visits (except for ED visits) did not rise correspondingly. Although such restructuring resulted in more people dying out of hospital, it does not appear FPs responded by providing more medical care to them in the community

Mindfulness and fear of hypoglycaemia in parents of children with Type 1 diabetes: results from Diabetes MILES Youth - The Netherlands

AimsTo identify the sociodemographic and clinical correlates of fear of hypoglycaemia among parents of children (aged 4&ndash;18 years) with Type 1 diabetes and to examine the relationships between parental fear of hypoglycaemia, mindfulness and mindful parenting.MethodsSociodemographic, self‐reported clinical and psychological data were extracted from the cross‐sectional Diabetes MILES Youth &ndash; The Netherlands dataset. Questionnaires included the Hypoglycaemia Fear Survey &ndash; Parent Worry (parental fear of hypoglycaemia), the Freiburg Mindfulness Inventory &ndash; Short version (mindfulness) and the Interpersonal Mindfulness in Parenting Scale (mindful parenting).ResultsA total of 421 parents (359 mothers) participated. Hierarchical linear regression analyses showed that greater parental fear of hypoglycaemia was related to younger parental age, low educational level, non‐Dutch nationality, more frequent blood glucose monitoring, and less general mindfulness. Adding mindful parenting to the model negated the previous contribution of general mindfulness. In this model, lower mindful parenting was related to greater parental fear of hypoglycaemia. In particular, parents with an increased ability to be less judgemental of themselves as parents and less reactive to emotions within parenting interactions reported less fear of hypoglycaemia. In total, 21% of the variance in parental fear of hypoglycaemia was explained.ConclusionParental fear of hypoglycaemia was associated largely with parental characteristics, including non‐modifiable sociodemographics (i.e. age, education, nationality) and modifiable psychological factors (i.e. mindful parenting). These findings suggest that it is important to further explore mindfulness‐based interventions for parents to reduce fear of hypoglycaemia next to interventions to reduce hypoglycaemia.<br /

UPRIGHT, a resilience-based intervention to promote mental well-being in schools: study rationale and methodology for a European randomized controlled trial

Background: Adolescence is crucial period for laying the foundations for healthy development and mental wellbeing. The increasing prevalence of mental disorders amongst adolescents makes promotion of mental well-being and prevention interventions at schools important. UPRIGHT (Universal Preventive Resilience Intervention Globally implemented in schools to improve and promote mental Health for Teenagers) is designed as a whole school approach (school community, students and families) to promote a culture of mental well-being and prevent mental disorders by enhancing resilience capacities. The present article aims at describing the rationale, conceptual framework, as well as methodology of implementation and evaluation of the UPRIGHT intervention.Methods: UPRIGHT project is a research and innovation project funded by the European Union's Horizon 2020 Research and Innovation programme under grant agreement No. 754919 (Duration: 48 months). The theoretical framework has been developed by an innovative and multidisciplinary approach using a co-creation process inside the UPRIGHT Consortium (involving seven institutions from Spain, Italy, Poland, Norway, Denmark, and Iceland). Resulted is the UPRIGHT programme with 18 skills related to 4 components: Mindfulness, Coping, Efficacy and Social and Emotional Learning. Among the five Pan-European regions, 34 schools have been currently involved (17 control; 17 intervention) and around 6000 adolescents and their families are foreseen to participate along a 3-year period of evaluation. Effectiveness of the intervention will be evaluated as a randomized controlled trial including quantitative and qualitative analysis in the five Pan-European regions representative of the cultural and socioeconomic diversity. The cost-effectiveness assessment will be performed by simulation modelling methods.Discussion: We expect a short- to medium-term improvement of mental well-being in adolescents by enhancing resilience capacities. The study may provide robust evidence on intrapersonal, familiar and social environmental resilience factors promoting positive mental well-being.Trial registration: ClinicalTrials.gov Identifier: NCT03951376. Registered 15 May 2019

Malaria knowledge and agricultural practices that promote mosquito breeding in two rural farming communities in Oyo State, Nigeria

<p>Abstract</p> <p>Background</p> <p>Agricultural practices such as the use of irrigation during rice cultivation, the use of ponds for fish farming and the storage of water in tanks for livestock provide suitable breeding grounds for anthropophylic mosquitoes. The most common anthropophylic mosquito in Nigeria which causes much of the morbidity and mortality associated with malaria is the anopheles mosquito. Farmers are therefore at high risk of malaria - a disease which seriously impacts on agricultural productivity. Unfortunately information relating to agricultural practices and farmers' behavioural antecedent factors that could assist malaria programmers plan and implement interventions to reduce risk of infections among farmers is scanty. Farmers' knowledge about malaria and agricultural practices which favour the breeding of mosquitoes in Fashola and Soku, two rural farming communities in Oyo State were therefore assessed in two rural farming communities in Oyo State.</p> <p>Methods</p> <p>This descriptive cross-sectional study involved the collection of data through the use of eight Focus Group Discussions (FGDs) and the interview of 403 randomly selected farmers using semi-structured questionnaires. These sets of information were supplemented with observations of agricultural practices made in 40 randomly selected farms. The FGD data were recorded on audio-tapes, transcribed and subjected to content analysis while the quantitative data were analyzed using descriptive and inferential statistics.</p> <p>Results</p> <p>Most respondents in the two communities had low level of knowledge of malaria causation as only 12.4% stated that mosquito bite could transmit the disease. Less than half (46.7%) correctly mentioned the signs and symptoms of malaria as high body temperature, body pains, headache, body weakness and cold/fever. The reported main methods for preventing mosquito bites in the farming communities included removal of heaps of cassava tuber peelings (62.3%), bush burning/clearing (54.6%) and clearing of ditches (33.7%). The dumping of cassava tuber peelings which allows the collection of pools of water in the farms storage of peeled cassava tubers soaked in water in uncovered plastic containers, digging of trenches, irrigation of farms and the presence of fish ponds were the observed major agricultural practices that favoured mosquito breeding on the farms. A significant association was observed between respondents' knowledge about malaria and agricultural practices which promote mosquito breeding. Respondents' wealth quintile level was also seen to be associated with respondents' knowledge about malaria and agricultural practices which promote mosquito breeding.</p> <p>Conclusion</p> <p>Farmers' knowledge of malaria causation and signs and symptoms was low, while agricultural practices which favour mosquito breeding in the farming communities were common. There is an urgent need to engage farmers in meaningful dialogue on malaria reduction initiatives including the modification of agricultural practices which favour mosquito breeding. Multiple intervention strategies are needed to tackle the factors related to malaria prevalence and mosquito abundance in the communities.</p

Retrospective analysis of molecular scores for the prediction of distant recurrence according to baseline risk factors

This work was funded by grants from Cancer Research UK (programme Grant C569-A16891), the Royal Marsden NIHR Biomedical Research Centre, and AstraZenec

Improved HIV and Substance Abuse Treatment Outcomes for Released HIV-Infected Prisoners: The Impact of Buprenorphine Treatment

HIV-infected prisoners fare poorly after release. Though rarely available, opioid agonist therapy (OAT) may be one way to improve HIV and substance abuse treatment outcomes after release. Of the 69 HIV-infected prisoners enrolled in a randomized controlled trial of directly administered antiretroviral therapy, 48 (70%) met DSM-IV criteria for opioid dependence. Of these, 30 (62.5%) selected OAT, either as methadone (N = 7, 14.5%) or buprenorphine/naloxone (BPN/NLX; N = 23, 48.0%). Twelve-week HIV and substance abuse treatment outcomes are reported as a sub-study for those selecting BPN/NLX. Retention was high: 21 (91%) completed BPN/NLX induction and 17 (74%) remained on BPN/NLX after 12 weeks. Compared with baseline, the proportion with a non-detectable viral load (61% vs 63% log10 copies/mL) and mean CD4 count (367 vs 344 cells/mL) was unchanged at 12 weeks. Opiate-negative urine testing remained 83% for the 21 who completed induction. Using means from 10-point Likert scales, opioid craving was reduced from 6.0 to 1.8 within 3 days of BPN/NLX induction and satisfaction remained high at 9.5 throughout the 12 weeks. Adverse events were few and mild. BPN/NLX therapy was acceptable, safe and effective for both HIV and opioid treatment outcomes among released HIV-infected prisoners. Future randomized controlled trials are needed to affirm its benefit in this highly vulnerable population

Efficacy and Safety of an Injectable Combination Hormonal Contraceptive for Men

CONTEXT: The development of a safe and effective reversible method of male contraception is still an unmet need. OBJECTIVE: Evaluation of suppression of spermatogenesis and contraceptive protection by coadministered im injections of progestogen and testosterone. DESIGN: Prospective multicentre study. SETTING: Ten study centers. PARTICIPANTS: Healthy men, aged 18-45 years, and their 18- to 38-year-old female partners, both without known fertility problems. INTERVENTION: Intramuscular injections of 200-mg norethisterone enanthate combined with 1000-mg testosterone undecanoate, administered every 8 weeks. MAIN OUTCOMES MEASURES: Suppression of spermatogenesis by ejaculate analysis, contraceptive protection by pregnancy rate. RESULTS: Of the 320 participants, 95.9 of 100 continuing users (95% confidence interval [CI], 92.8-97.9) suppressed to a sperm concentration less than or equal to 1 million/mL within 24 weeks (Kaplan-Meier method). During the efficacy phase of up to 56 weeks, 4 pregnancies occurred among the partners of the 266 male participants, with the rate of 1.57 per 100 continuing users (95% CI, 0.59-4.14). The cumulative reversibility of suppression of spermatogenesis after 52 weeks of recovery was 94.8 per 100 continuing users (95% CI, 91.5-97.1). The most common adverse events were acne, injection site pain, increased libido, and mood disorders. Following the recommendation of an external safety review committee the recruitment and hormone injections were terminated early. CONCLUSIONS: The study regimen led to near-complete and reversible suppression of spermatogenesis. The contraceptive efficacy was relatively good compared with other reversible methods available for men. The frequencies of mild to moderate mood disorders were relatively high

Fear of hypoglycaemia: defining a minimum clinically important difference in patients with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>To explore the concept of the Minimum Clinically Important Difference (MID) of the Worry Scale of the Hypoglycaemia Fear Survey (HFS-II) and to quantify the clinical importance of different types of patient-reported hypoglycaemia.</p> <p>Methods</p> <p>An observational study was conducted in Germany with 392 patients with type 2 diabetes mellitus treated with combinations of oral anti-hyperglycaemic agents. Patients completed the HFS-II, the Treatment Satisfaction Questionnaire for Medication (TSQM), and reported on severity of hypoglycaemia. Distribution- and anchor-based methods were used to determine MID. In turn, MID was used to determine if hypoglycaemia with or without need for assistance was clinically meaningful compared to having had no hypoglycaemia.</p> <p>Results</p> <p>112 patients (28.6%) reported hypoglycaemic episodes, with 15 patients (3.8%) reporting episodes that required assistance from others. Distribution- and anchor-based methods resulted in MID between 2.0 and 5.8 and 3.6 and 3.9 for the HFS-II, respectively. Patients who reported hypoglycaemia with (21.6) and without (12.1) need for assistance scored higher on the HFS-II (range 0 to 72) than patients who did not report hypoglycaemia (6.0).</p> <p>Conclusion</p> <p>We provide MID for HFS-II. Our findings indicate that the differences between having reported no hypoglycaemia, hypoglycaemia without need for assistance, and hypoglycaemia with need for assistance appear to be clinically important in patients with type 2 diabetes mellitus treated with oral anti-hyperglycaemic agents.</p