Amelogenesis imperfecta (AI) is the name given to a heterogeneous group of conditions characterized by inherited developmental enamel defects. AI enamel is abnormally thin, soft, fragile, pitted ...and/or badly discolored, with poor function and aesthetics, causing patients problems such as early tooth loss, severe embarrassment, eating difficulties, and pain. It was first described separately from diseases of dentine nearly 80 years ago, but the underlying genetic and mechanistic basis of the condition is only now coming to light. Mutations in the gene
, encoding an extracellular matrix protein secreted by ameloblasts during enamel formation, were first identified as a cause of AI in 1991. Since then, mutations in at least eighteen genes have been shown to cause AI presenting in isolation of other health problems, with many more implicated in syndromic AI. Some of the encoded proteins have well documented roles in amelogenesis, acting as enamel matrix proteins or the proteases that degrade them, cell adhesion molecules or regulators of calcium homeostasis. However, for others, function is less clear and further research is needed to understand the pathways and processes essential for the development of healthy enamel. Here, we review the genes and mutations underlying AI presenting in isolation of other health problems, the proteins they encode and knowledge of their roles in amelogenesis, combining evidence from human phenotypes, inheritance patterns, mouse models, and
studies. An LOVD resource (http://dna2.leeds.ac.uk/LOVD/) containing all published gene mutations for AI presenting in isolation of other health problems is described. We use this resource to identify trends in the genes and mutations reported to cause AI in the 270 families for which molecular diagnoses have been reported by 23rd May 2017. Finally we discuss the potential value of the translation of AI genetics to clinical care with improved patient pathways and speculate on the possibility of novel treatments and prevention strategies for AI.
Amelogenesis is the process of dental enamel formation, leading to the deposition of the hardest tissue in the human body. This process requires the intricate regulation of ion transport and ...controlled changes to the pH of the developing enamel matrix. The means by which the enamel organ regulates pH during amelogenesis is largely unknown. We identified rare homozygous variants in GPR68 in three families with amelogenesis imperfecta, a genetically and phenotypically heterogeneous group of inherited conditions associated with abnormal enamel formation. Each of these homozygous variants (a large in-frame deletion, a frameshift deletion, and a missense variant) were predicted to result in loss of function. GPR68 encodes a proton-sensing G-protein-coupled receptor with sensitivity in the pH range that occurs in the developing enamel matrix during amelogenesis. Immunohistochemistry of rat mandibles confirmed localization of GPR68 in the enamel organ at all stages of amelogenesis. Our data identify a role for GPR68 as a proton sensor that is required for proper enamel formation.
Sleep health is best described by the co-occurrence of various dimensions (e.g., regularity, daytime alertness, satisfaction, efficiency, duration) but is rarely measured this way. Information is ...needed regarding common within-person patterns of sleep characteristics among adults and their relative healthiness.
To deepen understanding of healthy and unhealthy sleep, the present study aimed to uncover multidimensional sleep profiles in adults and their associations with a variety of psychological and physical well-being outcomes.
Survey data from 4622 adults who participated in the Midlife in the United States (MIDUS) project was used to identify latent sleep profiles across five core sleep dimensions. Adjusting for individual sleep dimensions and sociodemographic covariates, General Linear Models were used to test the associations of sleep profile membership with hedonic and eudemonic well-being and chronic physical conditions.
Four latent sleep profiles were revealed, good sleepers, sufficient but irregular sleepers, nappers, and short, dissatisfied, and inefficient sleepers. The profiles differentially related to well-being outcomes above and beyond individual sleep dimensions and sociodemographic covariates. Good sleepers generally reported the best outcomes, and short, dissatisfied, and inefficient sleepers generally reported the worst outcomes.
Four common sleep profiles describe adults' holistic sleep experiences and predict a variety of well-being outcomes beyond other known predictors. In adulthood, healthy sleep may involve sufficient sleep across all dimensions whereas unhealthy sleep may involve insufficient sleep across three key dimensions: duration, satisfaction, and efficiency.
•Latent profile analysis revealed four multidimensional sleep phenotypes in adults.•Sleep profiles predicted well-being above and beyond individual sleep dimensions.•Good sleepers were the most common and reported the best well-being.•Nappers and irregular sleepers reported comparatively moderate well-being.•Co-occurring short, dissatisfying, and inefficient sleep may indicate poor well-being.
Safety-netting has become best practice when dealing with diagnostic uncertainty in primary care. Its use, however, is highly varied and a lack of evidence-based guidance on its communication could ...be harming its effectiveness and putting patient safety at risk.
To use a realist review method to produce a programme theory of safety-netting, that is, advice and support provided to patients when diagnosis or prognosis is uncertain, in primary care.
Five electronic databases, web searches, and grey literature were searched for studies assessing outcomes related to understanding and communicating safety-netting advice or risk communication, or the ability of patients to self-care and re-consult when appropriate. Characteristics of included documents were extracted into an Excel spreadsheet, and full texts uploaded into NVivo and coded. A random 10% sample was independently double -extracted and coded. Coded data wasere synthesised and itstheir ability to contribute an explanation for the contexts, mechanisms, or outcomes of effective safety-netting communication considered. Draft context, mechanism and outcome configurations (CMOCs) were written by the authors and reviewed by an expert panel of primary care professionals and patient representatives.
95 documents contributed to our CMOCs and programme theory. Effective safety-netting advice should be tailored to the patient and provide practical information for self-care and reconsultation. The importance of ensuring understanding and agreement with advice was highlighted, as was consideration of factors such as previous experiences with healthcare, the patient's personal circumstances and the consultation setting. Safety-netting advice should be documented in sufficient detail to facilitate continuity of care.
We present 15 recommendations to enhance communication of safety-netting advice and map these onto established consultation models. Effective safety-netting communication relies on understanding the information needs of the patient, barriers to acceptance and explanation of the reasons why the advice is being given. Reduced continuity of care, increasing multimorbidity and remote consultations represent threats to safety-netting communication.
The Covid‐19 pandemic has driven the fastest changes to higher education across the globe, necessitated by social distancing measures preventing face‐to‐face teaching. This has led to an almost ...immediate switch to distance learning by higher education institutions. Anatomy faces some unique challenges. Intrinsically, anatomy is a three‐dimensional subject that requires a sound understanding of the relationships between structures, often achieved by the study of human cadaveric material, models, and virtual resources. This study sought to identify the approaches taken in the United Kingdom and Republic of Ireland to deliver anatomical education through online means. Data were collected from 14 different universities in the United Kingdom and Republic of Ireland and compared adopting a thematic analysis approach. Once themes were generated, they were collectively brought together using a strength, weakness, opportunity, threat (SWOT) analysis. Key themes included the opportunity to develop new online resources and the chance to engage in new academic collaborations. Academics frequently mentioned the challenge that time constrains could place on the quality and effectiveness of these resources; especially as in many cases the aim of these resources was to compensate for a lack of exposure to cadaveric exposure. Comparisons of the actions taken by multiple higher education institutions reveal the ways that academics have tried to balance this demand. Discussions will facilitate decisions being made by higher education institutions regarding adapting the curriculum and assessment methods in anatomy.
This paper reports results from an Australian study into how teachers see features of quality in student work and connect these to next‐step teaching. Data were drawn from a national 3 year project ...investigating teacher judgement using A–E standards. The project developed scaled exemplars of authentic student written performance assessments to support teacher judgement and inform next‐step teaching and learning. Fifty‐seven participants created evaluative explanations of grading decisions (i.e. cognitive commentaries), wrote reflective responses and participated in online meeting discussions of their cognitive commentaries. These data were examined using qualitative content and thematic analyses. Findings highlighted how stated standards influence teachers’ judgements of student work. Variation was evident in teachers’ focus on (1) content (i.e. core skills vs. extended thinking), (2) specificity of improvement points and suggested teaching strategies and (3) the connection between identified areas for improvement and teaching strategies. Most teachers were able to identify specific points for improvement. However, in the main, they selected next‐step teaching strategies that were general rather than targeted and specific. Teachers reflected that structured analysis helped direct their thinking and judgements, targeting attention on next‐step teaching. The results suggested that teacher education and professional development should focus on supporting teachers to link specific teaching strategies to identified student weaknesses. This study found that artefacts, such as cognitive commentaries that connect assessment, teaching and learning, can help build professional knowledge and expertise, which remain key components of teacher assessment literacy.
Growing evidence for the role of GPs' gut feelings in cancer diagnosis raises questions about their origin and role in clinical practice.
To explore the origins of GPs' gut feelings for cancer, their ...use, and their diagnostic utility.
Systematic review and meta-analysis of international research on GPs' gut feelings in primary care.
Six databases were searched from inception to July 2019, and internet searches were conducted. A segregated method was used to analyse, then combine, quantitative and qualitative findings.
Twelve articles and four online resources were included that described varied conceptualisations of gut feelings. Gut feelings were often initially associated with patients being unwell, rather than with a suspicion of cancer, and were commonly experienced in response to symptoms and non-verbal cues. The pooled odds of a cancer diagnosis were four times higher when gut feelings were recorded (OR 4.24, 95% confidence interval = 2.26 to 7.94); they became more predictive of cancer as clinical experience and familiarity with the patient increased. Despite being included in some clinical guidelines, GPs had varying experiences of acting on gut feelings as some specialists questioned their diagnostic value. Consequently, some GPs ignored or omitted gut feelings from referral letters, or chose investigations that did not require specialist approval.
GPs' gut feelings for cancer were conceptualised as a rapid summing up of multiple verbal and non-verbal patient cues in the context of the GPs' clinical knowledge and experience. Triggers of gut feelings not included in referral guidance deserve further investigation as predictors of cancer. Non-verbal cues that trigger gut feelings appear to be reliant on continuity of care and clinical experience; they tend to remain poorly recorded and are, therefore, inaccessible to researchers.
Background
The relationships between physical activity (PA) and both cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) have predominantly been estimated using categorical measures of ...PA, masking the shape of the dose‐response relationship. In this systematic review and meta‐analysis, for the very first time we are able to derive a single continuous PA metric to compare the association between PA and CVD/T2DM, both before and after adjustment for a measure of body weight.
Methods and Results
The search was applied to MEDLINE and EMBASE electronic databases for all studies published from January 1981 to March 2014. A total of 36 studies (3 439 874 participants and 179 393 events, during an average follow‐up period of 12.3 years) were included in the analysis (33 pertaining to CVD and 3 to T2DM). An increase from being inactive to achieving recommended PA levels (150 minutes of moderate‐intensity aerobic activity per week) was associated with lower risk of CVD mortality by 23%, CVD incidence by 17%, and T2DM incidence by 26% (relative risk RR, 0.77 0.71–0.84), (RR, 0.83 0.77–0.89), and (RR, 0.74 0.72–0.77), respectively, after adjustment for body weight.
Conclusions
By using a single continuous metric for PA levels, we were able to make a comparison of the effect of PA on CVD incidence and mortality including myocardial infarct (MI), stroke, and heart failure, as well as T2DM. Effect sizes were generally similar for CVD and T2DM, and suggested that the greatest gain in health is associated with moving from inactivity to small amounts of PA.
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