Novel polymorphisms influencing transcription of the human CHRM2 gene in airway smooth muscle

Muscarinic receptors are a functionally important family of G-protein-coupled receptors. Using a combination of rapid amplification of 5′ cDNA ends and reporter gene assays, we characterized the 5′ untranslated region of the CHRM2 gene as expressed in human airway smooth muscle (HASM) cells. A splice site is present 46 bp upstream from the ATG start codon. Five exons with alternative splicing patterns are present upstream of this splice site, separated by introns ranging from 87 bp to > 145 kb. There is evidence for the gene being under the control of a TATA-less promoter with Sp1, GATA, and activator protein-2 binding sites. Multiple transcription start sites (TSSs) were identified. We identified a novel 0.5-kb hypervariable region located 648 bp upstream of the most 5′ TSS, a multiallelic (CA) tandem repeat 96 bp downstream of the most 5′ TSS, and a common C→A SNP located 136 bp upstream of the most 5′ TSS. Functional studies in primary HASM cells and the BEAS-2B cell line demonstrated highest promoter activity to be upstream of the most 3′ TSS, with potential repressor elements operating in a cell type-dependent manner, located upstream of the most 5′ TSS. We present functional data to show that the CA repeat may influence the transcription of the gene in HASM and BEAS-2B cells.peer-reviewe

The Impact of Shame, Self-Criticism and Social Rank on Eating Behaviours in Overweight and Obese Women Participating in a Weight Management Programme

Recent research has suggested that obesity is a stigmatised condition. Concerns with personal inferiority (social rank), shame and self-criticism may impact on weight management behaviours. The current study examined associations between social comparison (shame, self-criticism), negative affect and eating behaviours in women attending a community based weight management programme focused on behaviour change. 2,236 participants of the programme completed an online survey using measures of shame, self-criticism, social comparison, and weight-related affect, which were adapted to specifically address eating behaviour, weight and body shape perceptions. Correlation analyses showed that shame, self-criticism and social comparison were associated with negative affect. All of these variables were related to eating regulation and weight control (p < 0.001). Path analysis revealed that the association of shame, hated-self, and low self-reassurance on disinhibition and susceptibility to hunger was fully mediated by weight-related negative affect, even when controlling for the effect of depressive symptoms (p < 0.050 to p < 0.010). In addition, feelings of inadequacy and unfavourable social comparisons were associated with higher disinhibition and susceptibility to hunger, partially mediated through weight-related negative affect (p = 0.001). These variables were negatively associated with extent of weight loss during programme attendance prior to the survey, while self-reassurance and positive social comparisons were positively associated with the extent of weight loss prior to the survey (p < .050). Shame, self-criticism, and perceptions of inferiority may play a significant role in self-regulation of eating behaviour in overweight people trying to manage their weight

Mental health first aid for Indigenous Australians: using Delphi consensus studies to develop guidelines for culturally appropriate responses to mental health problems

<p>Abstract</p> <p>Background</p> <p>Ethnic minority groups are under-represented in mental health care services because of barriers such as poor mental health literacy. In 2007, the Mental Health First Aid (MHFA) program implemented a cultural adaptation of its first aid course to improve the capacity of Indigenous Australians to recognise and respond to mental health issues within their own communities. It became apparent that the content of this training would be improved by the development of best practice guidelines. This research aimed to develop culturally appropriate guidelines for providing first aid to an Australian Aboriginal or Torres Strait Islander person who is experiencing a mental health crisis or developing a mental illness.</p> <p>Methods</p> <p>A panel of Australian Aboriginal people who are experts in Aboriginal mental health, participated in six independent Delphi studies investigating depression, psychosis, suicidal thoughts and behaviours, deliberate self-injury, trauma and loss, and cultural considerations. The panel varied in size across the studies, from 20-24 participants. Panellists were presented with statements about possible first aid actions via online questionnaires and were encouraged to suggest additional actions not covered by the survey content. Statements were accepted for inclusion in a guideline if they were endorsed by ≥ 90% of panellists as <it>essential </it>or <it>important</it>. Each study developed one guideline from the outcomes of three Delphi questionnaire rounds. At the end of the six Delphi studies, participants were asked to give feedback on the value of the project and their participation experience.</p> <p>Results</p> <p>From a total of 1,016 statements shown to the panel of experts, 536 statements were endorsed (94 for depression, 151 for psychosis, 52 for suicidal thoughts and behaviours, 53 for deliberate self-injury, 155 for trauma and loss, and 31 for cultural considerations). The methodology and the guidelines themselves were found to be useful and appropriate by the panellists.</p> <p>Conclusion</p> <p>Aboriginal mental health experts were able to reach consensus about culturally appropriate first aid for mental illness. The Delphi consensus method could be useful more generally for consulting Indigenous peoples about culturally appropriate best practice in mental health services.</p

Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography, From Training Through Independent Practice.

BACKGROUND & AIMS: It is unclear whether participation in competency-based fellowship programs for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) results in high-quality care in independent practice. We measured quality indicator (QI) adherence during the first year of independent practice among physicians who completed endoscopic training with a systematic assessment of competence. METHODS: We performed a prospective multicenter cohort study of invited participants from 62 training programs. In phase 1, 24 advanced endoscopy trainees (AETs), from 20 programs, were assessed using a validated competence assessment tool. We used a comprehensive data collection and reporting system to create learning curves using cumulative sum analysis that were shared with AETs and trainers quarterly. In phase 2, participating AETs entered data into a database pertaining to every EUS and ERCP examination during their first year of independent practice, anchored by key QIs. RESULTS: By the end of training, most AETs had achieved overall technical competence (EUS 91.7%, ERCP 73.9%) and cognitive competence (EUS 91.7%, ERCP 94.1%). In phase 2 of the study, 22 AETs (91.6%) participated and completed a median of 136 EUS examinations per AET and 116 ERCP examinations per AET. Most AETs met the performance thresholds for QIs in EUS (including 94.4% diagnostic rate of adequate samples and 83.8% diagnostic yield of malignancy in pancreatic masses) and ERCP (94.9% overall cannulation rate). CONCLUSIONS: In this prospective multicenter study, we found that although competence cannot be confirmed for all AETs at the end of training, most meet QI thresholds for EUS and ERCP at the end of their first year of independent practice. This finding affirms the effectiveness of training programs. Clinicaltrials.gov ID NCT02509416

Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography, From Training Through Independent Practice.

BACKGROUND & AIMS: It is unclear whether participation in competency-based fellowship programs for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) results in high-quality care in independent practice. We measured quality indicator (QI) adherence during the first year of independent practice among physicians who completed endoscopic training with a systematic assessment of competence. METHODS: We performed a prospective multicenter cohort study of invited participants from 62 training programs. In phase 1, 24 advanced endoscopy trainees (AETs), from 20 programs, were assessed using a validated competence assessment tool. We used a comprehensive data collection and reporting system to create learning curves using cumulative sum analysis that were shared with AETs and trainers quarterly. In phase 2, participating AETs entered data into a database pertaining to every EUS and ERCP examination during their first year of independent practice, anchored by key QIs. RESULTS: By the end of training, most AETs had achieved overall technical competence (EUS 91.7%, ERCP 73.9%) and cognitive competence (EUS 91.7%, ERCP 94.1%). In phase 2 of the study, 22 AETs (91.6%) participated and completed a median of 136 EUS examinations per AET and 116 ERCP examinations per AET. Most AETs met the performance thresholds for QIs in EUS (including 94.4% diagnostic rate of adequate samples and 83.8% diagnostic yield of malignancy in pancreatic masses) and ERCP (94.9% overall cannulation rate). CONCLUSIONS: In this prospective multicenter study, we found that although competence cannot be confirmed for all AETs at the end of training, most meet QI thresholds for EUS and ERCP at the end of their first year of independent practice. This finding affirms the effectiveness of training programs. Clinicaltrials.gov ID NCT02509416

The mammalian gene function resource: the International Knockout Mouse Consortium.

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research

Development of mental health first aid guidelines for Aboriginal and Torres Strait Islander people experiencing problems with substance use: a Delphi study

<p>Abstract</p> <p>Background</p> <p>Problems with substance use are common in some Aboriginal communities. Although problems with substance use are associated with significant mortality and morbidity, many people who experience them do not seek help. Training in mental health first aid has been shown to be effective in increasing knowledge of symptoms and behaviours associated with seeking help. The current study aimed to develop culturally appropriate guidelines for providing mental health first aid to an Aboriginal or Torres Strait Islander person who is experiencing problem drinking or problem drug use (e.g. abuse or dependence).</p> <p>Methods</p> <p>Twenty-eight Aboriginal health experts participated in two independent Delphi studies (n = 22 problem drinking study, n = 21 problem drug use; 15 participated in both). Panellists were presented with statements about possible first aid actions via online questionnaires and were encouraged to suggest additional actions not covered by the content. Statements were accepted for inclusion in the guidelines if they were endorsed by ≥ 90% of panellists as either 'Essential' or 'Important'. At the end of the two Delphi studies, participants were asked to give feedback on the value of the project and their participation experience.</p> <p>Results</p> <p>From a total of 735 statements presented over two studies, 429 were endorsed (223 problem drinking, 206 problem drug use). Statements were grouped into sections based on common themes (n = 7 problem drinking, n = 8 problem drug use), then written into guideline documents. Participants evaluated the Delphi method employed, and the guidelines developed, as useful and appropriate for Aboriginal and Torres Strait Islander people.</p> <p>Conclusions</p> <p>Aboriginal health experts were able to reach consensus about culturally appropriate first aid for problems with substance use. Many first aid actions endorsed in the current studies were not endorsed in previous international Delphi studies, conducted on problem drinking and problem drug use in non-Indigenous people, highlighting the need for culturally specific first aid strategies to be employed when assisting Aboriginal or Torres Strait Islander people.</p

Speech production deficits in early readers: predictors of risk

Speech problems and reading disorders are linked, suggesting that speech problems may potentially be an early marker of later difficulty in associating graphemes with phonemes. Current norms suggest that complete mastery of the production of the consonant phonemes in English occurs in most children at around 6–7 years. Many children enter formal schooling (kindergarten) around 5 years of age with near-adult levels of speech production. Given that previous research has shown that speech production abilities and phonological awareness skills are linked in preschool children, we set out to examine whether this pattern also holds for children just beginning to learn to read, as suggested by the critical age hypothesis. In the present study, using a diverse sample, we explored whether expressive phonological skills in 92 5-year-old children at the beginning and end of kindergarten were associated with early reading skills. Speech errors were coded according to whether they were developmentally appropriate, position within the syllable, manner of production of the target sounds, and whether the error involved a substitution, omission, or addition of a speech sound. At the beginning of the school year, children with significant early reading deficits on a predictively normed test (DIBELS) made more speech errors than children who were at grade level. Most of these errors were typical of kindergarten children (e.g., substitutions involving fricatives), but reading-delayed children made more of these errors than children who entered kindergarten with grade level skills. The reading-delayed children also made more atypical errors, consistent with our previous findings about preschoolers. Children who made no speech errors at the beginning of kindergarten had superior early reading abilities, and improvements in speech errors over the course of the year were significantly correlated with year-end reading skills. The role of expressive vocabulary and working memory were also explored, and appear to account for some of these findings