Comparative effectiveness and cardiovascular safety of abaloparatide and teriparatide in postmenopausal women new to anabolic therapy: A US administrative claims database study.

Real-world evidence on the comparative effectiveness and safety of abaloparatide versus teriparatide in women with osteoporosis may help inform treatment decisions. Following 18 months of treatment, abaloparatide was comparable to teriparatide for prevention of nonvertebral fractures, resulted in a 22% risk reduction for hip fractures, and demonstrated similar cardiovascular safety. Osteoporotic fracture risk can be reduced with anabolic or antiresorptive medications. In addition to efficacy and safety data from controlled clinical trials, real-world evidence on comparative effectiveness and safety may help inform treatment decisions. INTRODUCTION: The real-world effectiveness of abaloparatide versus teriparatide on nonvertebral fracture (NVF) incidence and cardiovascular safety during the 19-month period after treatment initiation were evaluated (NCT04974723). METHODS: Anonymized US patient claims data from Symphony Health, Integrated Dataverse (IDV)®, May 1, 2017 to July 31, 2019, included women aged ≥ 50 years with ≥ 1 prescription of abaloparatide or teriparatide and no prior anabolic therapy. Most were enrolled in commercial and Medicare health plans. Index was the date of the initial prescription dispensed during the identification period. In 1:1 propensity score matched cohorts, time to first NVF following index date, major adverse cardiovascular events (MACE), and MACE + heart failure (HF) were compared between cohorts using a Cox proportional hazards model. RESULTS: Propensity score matching yielded 11,616 patients per cohort. Overall median age (interquartile range) was 67 (61, 75) years, and 25.6% had a fracture history. Over 19 months, 335 patients on abaloparatide and 375 on teriparatide had a NVF (hazard ratio [95% confidence interval]: 0.89 [0.77, 1.03]), and 121 and 154 patients, respectively, had a hip fracture [HR (95% CI): 0.78 (0.62, 1.00)]. The MACE and MACE + HF rates were similar between cohorts. CONCLUSIONS: Following 18 months of treatment, abaloparatide was comparable to teriparatide for prevention of NVF and similar cardiovascular safety was demonstrated between cohorts.

Improved preservation of ovarian tissue morphology that is compatible with antigen detection using a fixative mixture of formalin and acetic acid.

STUDY QUESTION: Can ovarian tissue morphology be better preserved whilst enabling histological molecular analyses following fixation with a novel fixative, neutral buffered formalin (NBF) with 5% acetic acid (referred to hereafter as Form-Acetic)? SUMMARY ANSWER: Fixation with Form-Acetic improved ovarian tissue histology compared to NBF in multiple species while still enabling histological molecular analyses. WHAT IS KNOWN ALREADY: NBF fixation results in tissue shrinkage in various tissue types including the ovary. Components of ovarian tissue, notably follicles, are particularly susceptible to NBF-induced morphological alterations and can lead to data misrepresentation. Bouin's solution (which contains 5% acetic acid) better preserves tissue architecture compared to NBF but is limited for immunohistochemical analyses. STUDY DESIGN, SIZE, DURATION: A comparison of routinely used fixatives, NBF and Bouin's, and a new fixative, Form-Acetic was carried out. Ovarian tissue was used from three different species: human (n = 5 patients), sheep (n = 3; 6 ovaries; 3 animals per condition) and mouse (n = 14 mice; 3 ovaries from 3 different animals per condition). PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian tissue from humans (aged 13 weeks to 32 years), sheep (reproductively young i.e. 3-6 months) and mice (10 weeks old) were obtained and fixed in 2 ml NBF, Bouin's or Form-Acetic for 4, 8, and 24 h at room temperature. Tissues were embedded and sectioned. Five-micron sections were stained with haemotoxylin and eosin (H&E) and the percentage of artefact (clear space as a result of shrinkage) between ovarian structures was calculated. Additional histological staining using Periodic acid-Schiff and Masson's trichrome were performed on 8 and 24 h NBF, Bouin's and Form-Acetic fixed samples to assess the compatibility of the new fixative with stains. On ovarian tissue fixed for both 8 and 24 h in NBF and Form-Acetic, immunohistochemistry (IHC) studies to detect FOXO3a, FoxL2, collagen IV, laminin and anti-Müllerian hormone (AMH) proteins were performed in addition to the terminal deoxynucleotidyl transferase nick end labelling (TUNEL) assay to determine the compatibility of Form-Acetic fixation with types of histological molecular analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Fixation in Form-Acetic improved ovarian tissue morphology compared to NBF from all three species and either slightly improved or was comparable to Bouin's for human, mouse and sheep tissues. Form-Acetic was compatible with H&E, Periodic acid-Schiff and Masson's trichrome staining and all proteins (FOXO3a, FoxL2, collagen IV and laminin and AMH) could be detected via IHC. Furthermore, Form-Acetic, unlike NBF, enabled antigen recognition for most of the proteins tested without the need for antigen retrieval. Form-Acetic also enabled the detection of damaged DNA via the TUNEL assay using fluorescence. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: In this study, IHC analysis was performed on a select number of protein types in ovarian tissue thus encouraging further studies to confirm the use of Form-Acetic in enabling the detection of a wider range of protein forms in addition to other tissue types. WIDER IMPLICATIONS OF THE FINDINGS: The simplicity in preparation of Form-Acetic and its superior preservative properties whilst enabling forms of histological molecular analyses make it a highly valuable tool for studying ovarian tissue. We, therefore, recommend that Form-Acetic replaces currently used fixatives and encourage others to introduce it into their research workflow. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Oxford Medical Research Council Doctoral Training Programme (Oxford MRC-DTP) grant awarded to B.D.B. (Grant no. MR/N013468/1), the Fondation Hoffmann supporting R.A. and the Petroleum Technology Development Fund (PTDF) awarded to B.V.A.

Fixation in Form-Acetic allows hyaluronic acid detection in mouse ovaries.

To visualise tissues to determine the presence of disease or simply to understand anatomy, it is important to preserve fresh tissue. Fixatives are chemical solutions that preserve tissues to enable microscopic evaluation. However, some fixatives introduce artefact such as shrinkage of cells. Recently, a new fixative, Form-Acetic, was developed that is superior for preserving the structure of ovary tissue and allows investigation of ovary composition. One component of the ovary is hyaluronic acid (HA), which plays a crucial role in normal ovary function and fertility. Importantly, HA is sensitive to different fixative solutions. Therefore, it is meaningful to verify whether Form-Acetic is suitable for detecting HA. In this study, adult mouse ovaries were fixed in Form-Acetic and HA was detected. All HA-containing structures in the ovary were clearly distinguished which proves that the novel fixative allows the detection of HA.

Characterizing patients initiating abaloparatide, teriparatide, or denosumab in a real-world setting: a US linked claims and EMR database analysis.

We characterized patients initiating abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) in a real-world clinical setting from a large medical and pharmacy claims database. Differences were noted in sex, age, pathologic fractures, comorbidity index, and prior bisphosphonate use for patients initiating ABL and TPTD compared with those receiving DMAB. INTRODUCTION: To characterize patients initiating abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) treatment in a real-world clinical setting. METHODS: Patients aged ≥ 18 years initiating ABL, TPTD, or DMAB between May 1, 2017, and September 24, 2018 (without receiving the same drug in the previous 12 months), were identified using the OM1 Data Cloud, which contains medical and pharmacy claims from approximately 200 million US patients. The index date was the date of initial prescription or dispensing for ABL, TPTD, or DMAB during the study period. RESULTS: During the study period, 2666 patients initiated ABL, 9210 TPTD, and 116,718 DMAB. Mean age (standard deviation) was 69.2 (10.6) years for the ABL cohort, 68.6 (11.3) for TPTD, and 72.1 (10.2) for DMAB (P < 0.001; ABL vs DMAB). Proportionally more patients initiating ABL were female (95.2% ABL, 86.9% TPTD, and 91.3% DMAB, P < 0.001 ABL vs TPTD or DMAB). Nearly twice as many patients initiating ABL (19.1%) and TPTD (18.8%) had a previous pathologic/fragility fracture vs DMAB (9.6%; P < 0.001 ABL vs DMAB). Fewer patients initiating ABL (36.3%) or TPTD (39.7%) had Charlson comorbidity index of ≥ 2 vs DMAB (48.4%; P < 0.001 ABL vs DMAB). Before initiating ABL, TPTD, or DMAB, 44.3%, 33.8%, and 33.9% of patients had prior osteoporosis treatment, respectively. Bisphosphonate use was more common before initiating ABL (19.2%) or TPTD (19.6%), than before initiating DMAB (16.6%; P < 0.001 ABL vs DMAB). CONCLUSIONS: Patients initiating ABL and TPTD differed in sex, age, pathologic fractures, comorbidity index, and prior bisphosphonate use compared with those initiating DMAB.

Osteoporotic fracture trends in a population of US managed care enrollees from 2007 to 2017.

This study expands on previous findings that hip fracture rates may no longer be declining. We found that age- and sex-adjusted fracture rates in the US plateaued or increased through mid-2017 in a population of commercially insured and Medicare Advantage health plan enrollees, in contrast to a decline from 2007 to 2013. INTRODUCTION: The purpose of this study was to evaluate fracture trends in US commercial and Medicare Advantage health plan members aged ≥ 50 years between 2007 and 2017. METHODS: Retrospective analysis of the Optum Research Database from January 1, 2007, to May 31, 2017. RESULTS: Of 1,841,263 patients identified with an index fracture, 930,690 were case-qualifying and included in this analysis. The overall age- and sex-adjusted fracture rate decreased from 14.67/1000 person-years (py) in 2007 to 11.79/1000 py in 2013, followed by a plateau for the next 3 years and then an increase to 12.50/1000 py in mid-2017. In females aged ≥ 65 years, fracture rates declined from 27.49/1000 py in 2007 to 22.08/1000 py in 2013, then increased to 24.92/1000 py in mid-2017. Likewise, fracture rates in males aged ≥ 65 years declined from 2007 (12.00/1000 py) to 2013 (10.72/1000 py), then increased to 12.04/1000 py in mid-2017. The age- and sex-adjusted fracture rates for most fracture sites declined from 2007 to 2013 by 3.7% per year (P = 0.310). CONCLUSIONS: Following a consistent decline in fracture rate from 2007 to 2013, trends from 2014 to 2017 indicate fracture rates are no longer declining and, for some fracture types, rates are rising.

Abaloparatide for risk reduction of nonvertebral and vertebral fractures in postmenopausal women with osteoporosis: a network meta-analysis.

This network meta-analysis assessed the efficacy of abaloparatide versus other treatment options to reduce the risk of fractures in women with postmenopausal osteoporosis. The analysis indicates that abaloparatide reduces the risk of fractures in women with postmenopausal osteoporosis versus placebo and compared with other treatment options. INTRODUCTION: This network meta-analysis (NMA) assessed the relative efficacy of abaloparatide versus other treatments to reduce the risk of fractures in women with postmenopausal osteoporosis (PMO). METHODS: PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published before December 20, 2017, that included women with PMO who were eligible to receive interventions for primary or secondary fracture prevention. The NMA was conducted by fracture site (vertebral [VF], nonvertebral [NVF], and wrist), with the relative risk (RR) of fracture versus placebo the main clinical endpoint. The NMA used fixed-effects and random-effects approaches. RESULTS: A total of 4978 articles were screened, of which 22 were included in the analysis. Compared with other treatments, abaloparatide demonstrated the greatest treatment effect relative to placebo in the VF network (RR = 0.13; 95% credible interval [CrI] 0.04-0.34), the NVF network (RR = 0.50; 95% CrI 0.28-0.85), and the wrist fracture network (RR = 0.39; CrI 0.15-0.90). Treatment ranking showed that abaloparatide had the highest estimated probability of preventing fractures in each of the networks (79% for VF, 70% for NVF, and 53% for wrist fracture) compared with other treatments. Individual networks demonstrated a good level of agreement with direct trial evidence and direct pair-wise comparisons. CONCLUSIONS: This NMA indicates that abaloparatide reduces the RR of VF, NVF, and wrist fracture in women with PMO with or without prior fracture versus placebo, compared with other treatment options. Limitations include that adverse events and drug costs were not considered, and that generalizability is limited to the trial populations and endpoints included in the NMA.

Strategies to reduce non-communicable diseases in the offspring: negative and positive in utero programming.

Non-communicable diseases (NCDs) are a major problem as they are the leading cause of death and represent a substantial economic cost. The 'Developmental Origins of Health and Disease Hypothesis' proposes that adverse stimuli at different life stages can increase the predisposition to these diseases. In fact, adverse in utero programming is a major origin of these diseases due to the high malleability of embryonic development. This review provides a comprehensive analysis of the scientific literature on in utero programming and NCDs highlighting potential medical strategies to prevent these diseases based upon this programming. We fully address the concept and mechanisms involved in this programming (anatomical disruptions, epigenetic modifications and microbiota alterations). We also examine the negative role of in utero programming on the increased predisposition of NCDs in the offspring, which introduces the passive medical approach that consists of avoiding adverse stimuli including an unhealthy diet and environmental chemicals. Finally, we extensively discuss active medical approaches that target the causes of NCDs and have the potential to significantly and rapidly reduce the incidence of NCDs. These approaches can be classified as direct in utero programming modifications and personalized lifestyle pregnancy programs; they could potentially provide transgenerational NCDs protection. Active strategies against NCDs constitute a promising tool for the reduction in NCDs.

Outcome of nutritional screening in the acute paediatric setting.

INTRODUCTION: Multiple nutritional risk assessment tools are available, but there are limited data on their application in the acute setting. We explored the validity of two tools in a tertiary Children's Hospital's acute unit and the cohort's nutritional status using WHO definitions. METHODS: Prospective study n=300 (median 38 months; 44.6% female; 25.7% ≤12 months). Participants had standard anthropometry measured, all were screened using the Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP), the Paediatric Malnutrition Screening Tool (PMST) (modified STAMP) and 125 were additionally screened using the Paediatric Yorkhill Malnutrition Screening (PYMS) tool. RESULTS: The percentages with medium/high nutritional risk were as follows: STAMP 73.1%, PMST 79.3% and PYMS 30%. Height/weight were normally distributed with: 3.4% stunted (height-for-age z-score <-2); aged ≤ 5 years, 6.8% wasted (weight-for-height z-score (WHZ) <-2), 17.9% overweight (WHZ 1-2) and 6.2% obese (WHZ >2); aged >5 years, 5.8% thin (body mass index (BMI)-z-score (BAZ) <-2), 17.3% overweight (BAZ 1-2) and 5.8% obese (BAZ >2). The tools showed poor specificity and variable sensitivities when compared with WHO malnutrition criteria, with positive predictive values of <50%. κ-Analysis also showed poor agreement between the tools and the WHO cut-offs. CONCLUSION: These results suggest that nutritional screening tools have poor sensitivity and are difficult to interpret in the acute setting. It may be more effective to include the assessment of weight and height and nutritional intake in the context of the acute presentation as part of routine clinical assessment rather than relying on screening tools to identify those at risk.

Dysregulation of follicle development in a mouse model of premature ovarian insufficiency.

Premature ovarian insufficiency (POI) occurs in 1% of reproductive-age women. The ovarian manifestation ranges from the presence of a variable population of follicles (follicular) to the absence of follicles (afollicular), and in the majority of cases the cause is unknown. A transgenic mouse model of follicular POI, the Double Mutant (DM), arises from oocyte-specific deletion of Mgat1 and C1galt1 required for the generation of O- and N-glycans. DM females are subfertile at 6 weeks, infertile by 9 weeks and exhibit POI by 12 weeks of age. In this study we investigate the cause of the reduced fertility at 6 weeks and infertility at 9 weeks of DM females. Ovary sections were used to analyse follicle and corpora lutea (CL) numbers, apoptosis, and levels of laminin and 3ß-hydroxysteroid dehydrogenase using immunohistochemistry. After POI, DM females unexpectedly remained sexually receptive. At both 6 and 9 weeks, DM ovaries contained more primary follicles, however, at 9 weeks DM follicles were proportionally healthier, revealed by TUNEL analysis compared with Controls. In 9 week DM ovaries (collected post-mating), secondary follicles had theca and basal lamina structure abnormalities, whilst preovulatory follicles failed to ovulate resulting in the presence of numerous luteinised unruptured follicles, indicative of ovulation failure. Finally, DM ovaries contained more regressing CL with decreased luteal cell apoptosis indicative of a defect in CL regression. Identifying these follicular modifications have provided insight into the aetiology of a model of POI and highlight targets to investigate with the hope of developing new fertility treatments.

A TaqMan-based multiplex real-time PCR assay for the simultaneous detection of Wuchereria bancrofti and Brugia malayi.

With the Global Program for the Elimination of Lymphatic Filariasis continuing to make strides towards disease eradication, many locations endemic for the causative parasites of lymphatic filariasis are realizing a substantial decrease in levels of infection and rates of disease transmission. However, with measures of disease continuing to decline, the need for time-saving and economical molecular diagnostic assays capable of detecting low levels of parasite presence is increasing. This need is greatest in locations co-endemic for both Wuchereria bancrofti and Brugia parasites because testing for both causative agents individually results in significant increases in labor and reagent costs. Here we describe a multiplex, TaqMan-based, real-time PCR assay capable of simultaneously detecting W. bancrofti and Brugia malayi DNA extracted from human bloodspots or vector mosquito pools. With comparable sensitivity to established singleplex assays, this assay provides significant cost and labor savings for disease monitoring efforts in co-endemic locations.

Tug of war in the haematopoietic stem cell niche: do myeloma plasma cells compete for the HSC niche?

In the adult mammal, normal haematopoiesis occurs predominantly in the bone marrow, where primitive haematopoietic stem cells (HSC) and their progeny reside in specialised microenvironments. The bone marrow microenvironment contains specific anatomical areas (termed niches) that are highly specialised for the development of certain blood cell types, for example HSCs. The HSC niche provides important cell-cell interactions and signalling molecules that regulate HSC self-renewal and differentiation processes. These same signals and interactions are also important in the progression of haematological malignancies, such as multiple myeloma (MM). This review provides an overview of the bone marrow microenvironment and its involvement in normal, physiological HSC maintenance and plasma cell growth throughout MM disease progression.

Magnetic resonance imaging for the study of ovarian follicles in the mouse.

Additional tools to analyze follicle development would be highly advantageous because current methods require sacrifice of animals at specific times and time-consuming sectioning of tissues for histologic analysis. Magnetic resonance imaging (MRI) may provide a less involved, faster and more cost-effective method to analyze follicles in whole ovaries. Fixed ovaries were collected at different stages of the estrus cycle and after stimulation with gonadotrophins (24 and 48 h post pregnant mares serum (PMSG), and 10 and 24 h post human chorionic gonadotrophin (hCG)) with or without administration of the contrast agent gadodiamide. The MR images were generated using a vertical-bore, 11.7 Tesla MR system. Analysis of the MR images revealed large antral follicles in fixed ovaries with the oocyte and cumulus mass identifiable within preovulatory follicles. The use of gadodiamide had no impact on the quality of MR images obtained. The fixed ovaries were paraffin embedded, sectioned, and hematoxylin stained. Follicles were counted using the MR images and the histology sections. Preovulatory follicle numbers determined using MR images were comparable to those using histology; however counts of smaller follicles were inconsistent. MRI of gonadotrophin-stimulated ovaries in situ did not reveal discernable ovarian structures. Therefore, MRI is a useful tool for studying whole fixed ovaries leaving the ovary intact for additional analyses or for selection of samples based on morphology. The MRI is also useful for identifying preovulatory follicles, although analysis of smaller follicles is not possible, and thus the potential exists for cyst analysis in mouse models of polycystic ovarian syndrome (PCOS).

Cytochrome P450 1 enzyme inhibition and anticancer potential of chromene amides from Amyris plumieri.

Cytochrome P450 (CYP) enzyme inhibitory properties of six chromenylated amide compounds (CAs) from Amyris plumieri are described. Inhibition of CYP microsomes (CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP3A4 and CYP2C19) was monitored using a fluorescent assay. Potent inhibition was found against CYP1A1 with IC(50) and K(i) for CA1 (acetamide), being the lowest at 1.547 ± 1.0 µM and 0.37 µM respectively, displaying non-competitive kinetics. The selectivity for CYP1A1 was increased in CA3 (butanamide), which also exhibited cytotoxicity against breast cancer cells, MCF7 with an IC(50) of 47.46 ± 1.62 µM. Structure-activity relationship studies provide insight at a molecular level for CAs with implications in chemoprevention and chemotherapy.

Proof of concept: a PhRMA position paper with recommendations for best practice.

Proof of concept (POC) may be defined as the earliest point in the drug development process at which the weight of evidence suggests that it is "reasonably likely" that the key attributes for success are present and the key causes of failure are absent. POC is multidimensional but is focused on attributes that, if not addressed, represent a threat to the success of the project in crucial areas such as safety, efficacy, pharmaceutics, and commercial and regulatory issues. The appropriate weight of evidence is assessed through the use of mathematical models and by evaluating the consequences of advancing a candidate drug that is not safe, effective, or commercially viable, vs. failing to advance a candidate that possesses these attributes. Tools for POC include biomarkers, targeted populations, pharmacokinetic (PK)/pharmacodynamic (PD) modeling, simulation, and adaptive study designs. Challenges to the success of POCs include a shortage of skilled personnel, failure to integrate multiple disciplines and information, and the demand made by organizations for certainty.

Dental therapy in the United Kingdom: part 4. Teamwork--is it working for dental therapists?

OBJECTIVES: To determine whether practising dental therapists, including dually qualified hygienist/therapists, considered themselves to be part of the clinical team and whether clinical work referred to them met with their expectations. METHODS: A postal survey enquired about work experiences of UK dental therapists, as previously described earlier in the series. RESULTS: While they certainly considered themselves to be part of the clinical team, the majority of respondents did not feel 'fully utilised'. Seventy percent of respondents felt that the dentist had more patients that could be referred and 55% thought that they could do more extensive work. There was concern that dentists lacked awareness of therapists' clinical potential, although some respondents highlighted very positive experiences in practice. CONCLUSIONS: Dental therapists feel that they are part of the clinical team but consider that their skills are not fully utilised in many cases. There is scope for raising awareness among dentists regarding the therapists' clinical potential as well as sharing ideas for good working practice both within individual clinical settings and between different practices.

Dental therapy in the United Kingdom: part 3. Financial aspects of current working practices.

OBJECTIVES: To enquire into current remuneration arrangements among UK dental therapists and to explore the nature of any financially related concerns. METHODS: Part of the postal survey of therapists described in the previous paper in this series. RESULTS: The majority of therapists (63%) often work in multiple locations and therefore may be in receipt of more than one type of payment mechanism. Two thirds of therapists are paid an hourly rate in at least one of the locations where they work; just over half are paid a fixed monthly amount and one third are self-employed. Nine percent of respondents were receiving performance-related pay, using goal setting, incentives and bonuses. A number of financially-related concerns were identified. CONCLUSION: Diverse payment systems were reported. Some aspects could present important implications for future recruitment and retention.

Dental therapy in the United Kingdom: part 2. A survey of reported working practices.

OBJECTIVES: To conduct a survey of current working practices of UK dental therapists following the changes in permitted duties, allowed clinical settings and the introduction of the new dental contract in England and Wales. METHODS: A piloted postal questionnaire was circulated in 2006 to all General Dental Council (GDC) registered therapists and those on the hygienists register possessing a dental therapy qualification. Two subsequent mailings were used to boost the response rate. RESULTS: There was an 80.6% response rate (n = 587). Ninety-eight percent of respondents were female. Average time since qualification was 17 years. Eighty percent (n = 470) of respondents were currently working as a dental therapist, 53% part-time. Of the 470, half were engaged entirely in general dental practice (GDP), one third in the salaried dental services (SDS), while others worked across different settings. Only 39% claimed to spend most of their time treating children. Recently qualified therapists more often worked in GDP (p <0.001). Overall, a wide range of clinical duties were performed, although there was concern about maintaining skills across all the competencies since qualification, while emphasis on hygiene work was a limiting factor for some. On the basis of the continued professional development (CPD) activities described over one year, only half would have met the GDC CPD requirements from August 2008 for dental care professionals (DCPs). CONCLUSIONS: More than half of therapists now work in GDP, compared with none six years previously. Many undertake a full range of duties. However, there was concern that some dentists use them for hygiene skills rather than across the whole range of their competencies, risking deskilling, while others reported their inability to gain employment as a therapist.

Dental therapy in the United Kingdom: part 1. Developments in therapists' training and role.

The number of students entering training for dental therapy has been increasing rapidly over the last few years. In practice, the scope of their work has increased, both in terms of permitted duties and their range of clinical settings. The possibilities for dental practitioners to work with therapists is therefore increasing, so it is important for them to be clear about therapists' potential capacity to provide added value to the dental team. This paper, which is the first of four covering aspects of dental therapy in the UK, traces the history of dental therapy together with the development of therapists' training opportunities and emerging competencies, up to the present. The subsequent three papers will describe aspects of a survey of dental therapists undertaken in late 2006.

Genetics of platelet reactivity in normal, healthy individuals.

BACKGROUND: The Platelet Function Analyzer-100 (PFA-100) is widely used to measure platelet reactivity in whole blood under high shear. OBJECTIVE: To characterize the genetic component of platelet reactivity among normal individuals, using the PFA-100. METHODS: We compared baseline platelet reactivity with sex, age, platelet count, hematocrit, plasma von Willebrand factor antigen (VWF:Ag), and alleles of seven candidate genes: integrin subunits alpha2 (ITGA2) and beta3 (ITGB3), platelet glycoproteins GPIbalpha (GP1BA) and GPVI (GP6), purinogenic receptors (P2RY1 and P2RY12) and cyclooxygenase-1 (COX1). RESULTS: Based on linear and logistic regression models, we report an inverse correlation between baseline closure time (CT) initiated by collagen plus epinephrine (CEPI) and plasma VWF:Ag level, ITGA2 807T and P2RY1 893C, and an inverse correlation between baseline CT initiated by collagen plus adenosine diphosphate (CADP) and P2RY1 893C or GP1BA -5C. CONCLUSIONS: These results indicate that genetic polymorphisms in ITGA2 and P2RY1 combine with plasma VWF:Ag levels to modulate baseline platelet reactivity in response to collagen plus EPI, while genetic differences in P2RY1 and GP1BA significantly effect platelet responses to collagen plus ADP. Our results demonstrate that the PFA-100 can be used to evaluate the effects of genetic predictors of platelet function.

A prototypical process for creating evidentiary standards for biomarkers and diagnostics.

A framework for developing evidentiary standards for qualification of biomarkers is a key need identified in the Food and Drug Administration's Critical Path Initiative. This article describes a systematic framework that was developed by Pharmaceutical Research and Manufacturers of America (PhRMA) committees and tested at a workshop in collaboration with the Food and Drug Administration and academia. With some necessary refinements, this could be applied to create an appropriately individualized evidentiary standard for any biomarker purpose.