Novel Candidate Regulators and Developmental Trajectory of Pituitary Thyrotropes.

The pituitary gland regulates growth, metabolism, reproduction, the stress response, uterine contractions, lactation, and water retention. It secretes hormones in response to hypothalamic input, end organ feedback, and diurnal cues. The mechanisms by which pituitary stem cells are recruited to proliferate, maintain quiescence, or differentiate into specific cell types, especially thyrotropes, are not well understood. We used single-cell RNA sequencing in juvenile P7 mouse pituitary cells to identify novel factors in pituitary cell populations, with a focus on thyrotropes and rare subtypes. We first observed cells coexpressing markers of both thyrotropes and gonadotropes, such as Pou1f1 and Nr5a1. This was validated in vivo by both immunohistochemistry and lineage tracing of thyrotropes derived from Nr5a1-Cre; mTmG mice and demonstrates that Nr5a1-progenitors give rise to a proportion of thyrotropes during development. Our data set also identifies novel factors expressed in pars distalis and pars tuberalis thyrotropes, including the Shox2b isoform in all thyrotropes and Sox14 specifically in Pou1f1-negative pars tuberalis thyrotropes. We have therefore used single-cell transcriptomics to determine a novel developmental trajectory for thyrotropes and potential novel regulators of thyrotrope populations.

RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases.

The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis and necroptosis. Its kinase activity has been implicated in a range of inflammatory, neurodegenerative, and oncogenic diseases. Here, we explore the effect of inhibiting RIP1 genetically, using knock-in mice that express catalytically inactive RIP1 D138N, or pharmacologically, using the murine-potent inhibitor GNE684. Inhibition of RIP1 reduced collagen antibody-induced arthritis, and prevented skin inflammation caused by mutation of Sharpin, or colitis caused by deletion of Nemo from intestinal epithelial cells. Conversely, inhibition of RIP1 had no effect on tumor growth or survival in pancreatic tumor models driven by mutant Kras, nor did it reduce lung metastases in a B16 melanoma model. Collectively, our data emphasize a role for the kinase activity of RIP1 in certain inflammatory disease models, but question its relevance to tumor progression and metastases.

The challenges of managing gout in primary care: Results of a best-practice audit.

BACKGROUND AND OBJECTIVES: The aim of this project was to determine the effects of a package of care for gout in primary care. METHOD: An audit of gout management in a single rural medical practice was undertaken before (in 2012) and after (in 2015) the introduction of the package of care reflecting guidelines in gout management. RESULTS: There was a statistically significant increase in the number of individuals commenced on allopurinol ≤100 mg/d and a decrease in the number commenced on allopurinol ≥200 mg/d (P <0.001). The number of times each patient had serum urate tested between 2012 and 2015 (median [range] 1 [0-3] versus 2 [0-10], respectively; P <0.001). Of those individuals who had at least one serum urate measurement, the number of individuals who were never at target urate was 43 out of 67 (64.2%) in 2012, compared with 52 out of 133 (39.1%) in 2015 (P = 0.001). DISCUSSION: A package of care can improve adherence to gout management guidelines in primary care.

The effects of location and low-molecular-weight heparin administration on deep vein thrombosis outcomes in trauma patients.

BACKGROUND: Deep vein thrombosis (DVT) is common after trauma. Pulmonary embolism (PE) is a feared complication of DVT. Standard doses of low-molecular-weight heparin (LMWH) are commonly used to prevent and treat DVT and PE. There is variable bioavailability of LMWH with standard therapy. The traditional concept that below-knee DVT is associated with a lower risk of subsequent PE may result in less aggressive therapy. The purposes of this study were to assess the rates of PE in above-knee versus below-knee DVT and longitudinally evaluate outcomes of DVT treated with LMWH therapy. METHODS: This was a retrospective review of patients at a university Level I trauma center during the years 2005 through 2010. Patients diagnosed with lower-extremity DVT were included in this study. Patients were classified by location of lower-extremity DVT and type of LMWH therapy received. All high-risk trauma patients were evaluated with weekly duplex Doppler ultrasonography. All duplex studies were reviewed for DVT resolution or improvement. Symptomatic patients were evaluated with computed tomographic angiography to rule out PE. Demographics, total length of hospital stay, length of intensive care unit stay, and Injury Severity Score (ISS) were collected. RESULTS: Three-hundred eight trauma patients with lower-extremity DVT were included. More patients developed below-knee DVT (65.6%) compared with above-knee DVT (34.4%). Increased length of hospital stay, intensive care unit stay, and higher ISS were noted in patients with above-knee DVT. More patients had below-knee DVT in the prophylactic dosing group. With LMWH therapy, three PEs occurred in patients in the prophylactic dosing group with below-knee DVT, and no PEs occurred in the therapeutic treatment group. The incidence of PE between patients with below-knee DVT compared with above-knee DVT overall was not different (3.3% and 4.7%, p = 0.59). To assess DVT outcomes, 157 of the 308 patients had serial duplex studies following diagnosis of lower-extremity DVT. The number of patients receiving either therapeutic or prophylactic LMWH was similar (51% and 49%). There was no difference in rates of resolution or improvement between LMWH dosing groups or location of DVT. CONCLUSION: In screened trauma patients, below-knee DVT is more common than above-knee DVT. There was no difference in the incidence of PE between groups. Standard prophylactic and therapeutic dosing of LMWH does not affect the rates of resolution or improvement of lower-extremity DVT. Rates of resolution and improvement of DVT is not dependent of location of lower-extremity DVT. LEVEL OF EVIDENCE: Therapeutic study, level IV; epidemiologic study, level III.

Appetite for life: an evaluation of a primary care lifestyle programme.

INTRODUCTION: Appetite for Life is a six-week primary care-based programme for women who are overweight, and aims to achieve long-term health gain through establishing healthy eating and physical activity patterns and a healthier weight. AIM: To evaluate the outcomes of Appetite for Life, a primary care-based healthy lifestyle programme for women who are overweight. METHODS: Two hundred and sixty-one women enrolled and consented to take part in the six-week Appetite for Life programme via general practice and were followed for 12 months. Eating behaviours and physical activity levels were measured at baseline, six weeks, six months and 12 months. Anthropometric and biomedical data was collected at visits to the participants' general practitioners at baseline and 12 months. RESULTS: Positive lifestyle changes were reported that were sustained for the duration of the 12-month follow-up period. Participants reported an increase in intake of fruit and vegetables, dairy products, healthy fats and an increased level of physical activity. There was also an increase in reported enjoyment and participation in exercise. Mean weight was maintained over this time period. There was a reduction in mean LDL and total plasma cholesterol. DISCUSSION: A healthy lifestyle programme offered through primary care that is based on a non-dieting approach may help overweight women develop and sustain positive lifestyle changes.

Comparison of abdominal damage control surgery in combat versus civilian trauma.

BACKGROUND: The majority of individuals who perform damage control surgery in the military arena are trained in civilian venues. Therefore, it is important to compare and contrast damage control performed in civilian and military settings. In contrast to civilian trauma, which is primarily caused by blunt injury and addressed at one or two surgical facilities, combat casualties primarily sustain explosion-related injuries and undergo treatment at multiple levels of care across continents. We aimed to compare patients undergoing abdominal damage control surgery across these two very different settings. METHODS: Parallel retrospective reviews were conducted over 2 years (2005-2006) in a combat setting and at a US Level I trauma center. Patients were examined during the first 7 days after injury. RESULTS: The civilian population (CP) was older (40 vs. 23; p < 0.01) with a higher injury severity score (35 vs. 27; p < 0.02). The CP experienced greater blunt injury than the military population (MP) (83 vs. 4%; p < 0.01). Explosion-related injury was only present in the MP (64%). At baseline, the CP presented with lower systolic blood pressure (108 vs. 126) and larger base deficit (9.8 vs. 6.5; p < 0.05). The MP underwent more surgeries (3.5 vs. 2.9; p = 0.02) with similar rates of fascial closure (48.7% vs. 70.0%; p = 0.11). Complication rates were similar between the CP and the MP (43% vs. 58%, respectively; p = 0.14). CONCLUSIONS: Military and civilian trauma patients who undergo damage control surgery experience similar fascial closure rates despite differing demographics and widely disparate mechanisms of injury. The MP undergoes a greater number of procedures than the CP, but complication rates do not differ between the groups.

Comparison of two school-based smoking prevention programs among South African high school students: results of a randomized trial.

BACKGROUND: Smoking rates are projected to increase substantially in developing countries such as South Africa. PURPOSE: The aim of this study was to test the efficacy of two contrasting approaches to school-based smoking prevention in South African youth compared to the standard health education program. One experimental program was based on a skills training/peer resistance model and the other on a harm minimization model. METHOD: Thirty-six public schools from two South African provinces, KwaZulu-Natal and the Western Cape, were stratified by socioeconomic status and randomized to one of three groups. Group 1 (comparison) schools (n = 12) received usual tobacco use education. Group 2 schools (n = 12) received a harm minimization curriculum in grades 8 and 9. Group 3 schools (n = 12) received a life skills training curriculum in grades 8 and 9. The primary outcome was past month use of cigarettes based on a self-reported questionnaire. RESULT: Five thousand two hundred sixty-six students completed the baseline survey. Of these, 4,684 (89%) completed at least one follow-up assessment. The net change in 30-day smoking from baseline to 2-year follow-up in the control group was 6% compared to 3% in both harm minimization (HM) and life skills training (LST) schools. These differences were not statistically significant. Intervention response was significantly moderated by both gender and race. The HM intervention was more effective for males, whereas the life skills intervention was more effective for females. For black African students, the strongest effect was evident for the HM intervention, whereas the strongest intervention effect for "colored" students was evident for the LST group. CONCLUSION: The two experimental curricula both produced similar overall reductions in smoking prevalence that were not significantly different from each other or the control group. However, the impact differed by gender and race, suggesting a need to tailor tobacco and drug use prevention programs. More intensive intervention, in the classroom and beyond, may be needed to further impact smoking behavior.

Translating an adolescent smoking cessation program into policy and practice in an Australian context.

Although Australia's restrictive tobacco control policies have made it an international leader in reducing smoking prevalence, and only 7% of teens smoke weekly, cessation efforts are still needed among adolescents. Of the campaigns and programs implemented in Australia to reduce this problem among adolescents, most have provided only abstinence messages and few have been effectively evaluated and translated into policy and practice. This article describes the translation of a harm minimization cessation program for teens, the Smoking Cessation for Youth Project (SCYP), derived from an approach developed with adults. In addition, the article describes the unique sociopolitical context of Australia in which the SCYP program was developed and the significant conceptual, contextual, and methodological factors that enabled and limited this program's effective implementation and translation.

Does harm minimisation lead to greater experimentation? Results from a school smoking intervention trial.

INTRODUCTION AND AIMS: Declines in adolescent smoking prevalence have slowed recently, resulting in increased interest and literature in tobacco harm minimisation. To date, harm reduction strategies have focused largely on modifying the product and alternative (safer) mechanisms of nicotine delivery. There has been little exploration of primary harm minimisation to prevent the onset of regular smoking among young people. A major concern expressed about harm reduction interventions and young people is that they may increase experimentation among non-users. DESIGN AND METHODS: The Smoking Cessation for Youth Project was a 2-year school-based cluster randomised controlled trial conducted in 30 Western Australian schools. Results on the primary outcome showed a significant reduction in regular smoking among 4636 13-15-year-olds receiving a harm minimisaton versus standard intervention. This paper addresses the intervention effects on 2078 students who had not smoked at baseline. RESULTS: At 20-month follow-up, smoking initiation was slightly lower among intervention students than comparison students (who received a largely abstinence-based intervention), although this difference did not attain statistical significance (OR=0.86; 95% confidence interval: 0.68, 1.09). DISCUSSION AND CONCLUSIONS: This study provided limited evidence to suggest that harm minimisation is a superior approach to abstinence-based interventions for non-smokers. However, this intervention did not contribute to increased experimentation among non-smokers. Although more trials are required, these results indicate that fears of potential negative iatrogenic effects from school-based harm minimisation interventions may be unwarranted.

Issues in the assessment of cardiovascular risk in selected general practices in Canterbury, New Zealand.

AIMS: The aim was to audit patient records at selected general practices in Canterbury, New Zealand to assess the potential: (a) to improve identification and management of people with risk factors for cardiovascular disease (CVD); and (b) to develop a geographically distinct community database of CVD risk factor prevalence that could be used to plan public health programmes to improve cardiovascular health. METHODS: Patient records were audited in three general practices in a Canterbury rural town and information on cardiovascular risk factors recommended for the screening and management of CVD by the New Zealand Guidelines Group was extracted and entered into an electronic database. The data was analysed to assess the extent of recording of information on recommended risk factors. RESULTS: Most patient records contained information on smoking, blood pressure and lipid profiles. Low levels of information recording were found for physical activity, body mass index (BMI), and family history. There were statistically significant differences between general practices in the type and coverage of information recorded, even for patients with diagnosed cardiovascular disease. Because of deficiencies in information, it was not possible to calculate CVD risk using the guidelines for 43% of patients. Some practices remain reliant on paper records which make it extremely difficult to undertake a systematic programme of screening and management of CVD risk factors. CONCLUSIONS: Before it is practical to undertake a systematic screening programme for CVD risk factors in primary care, it is necessary to reduce reliance on paper records and to fully implement computerised patient management systems that allow for information storage and retrieval. In addition, it is essential to improve the systematic collection of key information in primary care that is used to assess risk of CVD.

Multilevel logistic regression modelling with correlated random effects: application to the Smoking Cessation for Youth study.

A multilevel logistic regression model is presented for the analysis of clustered and repeated binary response data. At the subject level, serial dependence is expected between repeated measures recorded on the same individual. At the cluster level, correlations of observations within the same subgroup are present due to the inherent hierarchical setting. Two random components are therefore incorporated explicitly within the linear predictor to account for the simultaneous heterogeneity and autoregressive structure. Application to analyse a set of longitudinal data from an adolescent smoking cessation intervention that motivated this study is illustrated.

A school-based harm minimization smoking intervention trial: outcome results.

AIMS: To determine the impact of a school-based harm minimization smoking intervention compared to traditional abstinence-based approaches. DESIGN, SETTING AND PARTICIPANTS: A school-based cluster randomized trial was conducted in Perth, Western Australia in 30 government high schools from 1999 to 2000. Over 4000 students were recruited to participate and schools were assigned randomly to either the harm minimization intervention or a standard abstinence-based programme. INTERVENTION: The harm minimization intervention comprised eight 1-hour lessons over 2 years, quitting support from school nurses and enactment of policies to support programme components. Comparison schools implemented standard abstinence-based programmes and policies. MEASURES: Cigarette smoking was categorized at two levels: regular smoking, defined as smoking on 4 or more days in the previous week; and 30-day smoking as any smoking within the previous month. FINDINGS: At immediate post-test (20 months post-baseline), after accounting for baseline differences, school-level clustering effects, socio-economic status, gender and family smoking, intervention students were less likely to smoke regularly [OR = 0.51, 95% confidence interval (CI) = 0.36, 0.71] or to have smoked within the previous 30 days (OR = 0.69, 95% CI = 0.53, 0.91). CONCLUSION: The school-based adolescent harm minimization intervention appears to have been more effective than the abstinence-based social influences programme at reducing regular smoking.

Adolescent smoking cessation: development of a school nurse intervention.

The purpose of this study was to examine the feasibility of a range of strategies to engage and to enhance secondary school nurse involvement in teenage smoking prevention and cessation. School nurses were willing to assist students to quit smoking, but they felt unprepared. Information provided by nurses involved in a three-stage review, pilot-testing, and trial design resulted in the development of a resource for nurses. This resource comprised individual student approaches (brief intervention based on motivational interviewing and written activities designed to help students examine their smoking behavior), approaches to assist parents (letter of support for parents of students who smoke), and school newsletter items. Each component of the resource was found by school nurses to be appropriate, useful, and complementary to their other school- wide approaches to assist adolescents to quit smoking. Nurses also reported an interest to expand or to enhance their smoking cessation role in the school.

School policy: what helps to reduce teenage smoking?

This study examined the degree to which different policy-based whole-school smoking actions were associated with cigarette smoking among 4,697 ninth-grade students in 31 schools in Perth, Australia. Smoking is banned in all schools in Western Australia. Cross-sectional self-report surveys measured student smoking prevalence and intensity and its correlates. Simultaneously, school policies and practices related to cigarette smoking were assessed by interviews with principals from each of the 31 schools. The relationship between school policies and practices and cigarette smoking were evaluated using logistic regression. After controlling for socioeconomic status, family smoking, and gender, no differences in "ever smoking" and "regular smoking" rates were seen among schools that reported having a school health policy, a school drug policy, or school health committee. Both ever smoking (p<.001) and regular smoking (p<.001) rates among students were lower at schools that provided education or counseling as well as discipline measures for students caught smoking at school, compared with schools that used discipline-only approaches. Although school health policies, drug policies, and health committees appeared to be associated with some psychosocial correlates of smoking, the associations of an education/counseling approach with these correlates was more consistent. These findings suggest that the actions taken to deal with students who violate smoking policy restrictions may be more important in reducing cigarette smoking than the presence of health or drug policies or health committees. Using education/counseling and discipline strategies rather than discipline only may help to reduce teenage smoking.