Decoding 22q11.2: prenatal profiling and first-trimester risk assessment in Danish nationwide cohort.

OBJECTIVES: To examine the distribution of nuchal translucency thickness (NT), free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in pregnancies with a fetal 22q11.2 aberration. Furthermore, the performance of combined first-trimester screening (cFTS) and a new risk algorithm targeting 22q11.2 deletions in detecting affected pregnancies was evaluated. Finally, prenatal malformations and pregnancy outcome were assessed. METHODS: This was a nationwide registry-based cohort study of all pregnancies that underwent prenatal screening with a due date between January 2008 and December 2018 in Denmark. All cases with a fetal 22q11.2 deletion or duplication (hg19 chr22:18.9mio-25.0mio) diagnosed pre- or postnatally or following pregnancy loss or termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal Medicine Database. Fetal and maternal characteristics, including cFTS results and pregnancy outcome, of pregnancies with any 22q11.2 deletion or duplication (LCR22-A to -H) and pregnancies with a classic deletion or duplication (LCR22-A to -D) diagnosed by chromosomal microarray were compared with those of a chromosomally normal reference group. A risk algorithm was developed for assessing patient-specific risks for classic 22q11.2 deletions based on NT, PAPP-A and ß-hCG. Detection rates and false-positive rates at different risk cut-offs were calculated. RESULTS: We included data on 143 pregnancies with a fetal 22q11.2 aberration, of which 97 were deletions (54 classic) and 46 were duplications (32 classic). NT was significantly increased in fetuses with a classic deletion (mean, 1.89 mm), those with any deletion (mean, 1.78 mm) and those with any duplication (mean, 1.86 mm) compared to the reference group (mean, 1.65 mm). ß-hCG multiples of the median (MoM) was decreased in all 22q11.2 subgroups compared with the reference group (mean, 1.02) and reached significance in pregnancies with a classic deletion and those with any deletion (mean, 0.77 and 0.71, respectively). PAPP-A MoM was significantly decreased in pregnancies with a classic duplication and those with any duplication (mean, 0.57 and 0.63, respectively), and was significantly increased in pregnancies with a classic deletion and those with any deletion (mean, 1.34 and 1.16, respectively), compared to reference pregnancies (mean, 1.01). The screen-positive rate by cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%) or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletions, but with a substantial increase in the false-positive rate. Structural malformations were detected in 41%, 35%, 17% and 25% of the pregnancies with a classic deletion, any deletion, classic duplication or any duplication, respectively. Pregnancy loss occurred in 40% of pregnancies with a classic deletion and 5% of those with a classic duplication diagnosed prenatally or following pregnancy loss. CONCLUSIONS: The distribution of cFTS markers in pregnancies with a classic 22q11.2 duplication resembles that of the common trisomies, with decreased levels of PAPP-A. However, classic 22q11.2 deletions are associated with increased levels of PAPP-A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions using targeted risk algorithms based on NT, PAPP-A and ß-hCG is limited. This demonstrates the capability, but also the limitations, of cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Evaluation of a training programme for Pharmacist Independent Prescribers in a care home medicine management intervention.

BACKGROUND: The provision of independent prescribing rights for United Kingdom (UK) pharmacists has enabled them to prescribe within their area of competence. The aim of this study was to evaluate an evidence-based training programme designed to prepare Pharmacist Independent Prescribers (PIPs) to safely and effectively assume responsibility for pharmaceutical care of older people in care homes in the UK, within a randomised controlled trial. METHODS: The training and competency assessment process included two training days, professional development planning against a bespoke competency framework, mentor support, and a viva with an independent General Practitioner (GP). Data on the PIPs' perceptions of the training were collected through evaluation forms immediately after the training days and through online questionnaires and interviews after delivery of the 6-month intervention. Using a mixed method approach each data set was analysed separately then triangulated providing a detailed evaluation of the process. Kaufman's Model of Learning Evaluation guided interpretations. RESULTS: All 25 PIPs who received the training completed an evaluation form (N = 25). Post-intervention questionnaires were completed by 16 PIPs and 14 PIPs took part in interviews. PIPs reported the training days and mentorship enabled them to develop a personalised portfolio of competence in preparation for discussion during a viva with an independent GP. Contact with the mentor reduced as PIPs gained confidence in their role. PIPs applied their new learning throughout the delivery of the intervention leading to perceived improvements in residents' quality of life and medicines management. A few PIPs reported that developing a portfolio of competence was time intensive, and that further training on leadership skills would have been beneficial. CONCLUSIONS: The bespoke training programme was fit for purpose. Mentorship and competency assessment were resource intensive but appropriate. An additional benefit was that many PIPs reported professional growth beyond the requirement of the study. TRIAL REGISTRATION: The definitive RCT was registered with the ISRCTN registry (registration number ISRCTN 17,847,169 ).

Accelerating ethics, empathy, and equity in geographic information science.

Science has traditionally been driven by curiosity and followed one goal: the pursuit of truth and the advancement of knowledge. Recently, ethics, empathy, and equity, which we term "the 3Es," are emerging as new drivers of research and disrupting established practices. Drawing on our own field of GIScience (geographic information science), our goal is to use the geographic approach to accelerate the response to the 3Es by identifying priority issues and research needs that, if addressed, will advance ethical, empathic, and equitable GIScience. We also aim to stimulate similar responses in other disciplines. Organized around the 3Es we discuss ethical issues arising from locational privacy and cartographic integrity, how our ability to build knowledge that will lead to empathy can be curbed by data that lack representativeness and by inadvertent inferential error, and how GIScientists can lead toward equity by supporting social justice efforts and democratizing access to spatial science and its tools. We conclude with a call to action and invite all scientists to join in a fundamentally different science that responds to the 3Es and mobilizes for change by engaging in humility, broadening measures of excellences and success, diversifying our networks, and creating pathways to inclusive education. Science united around the 3Es is the right response to this unique moment where society and the planet are facing a vast array of challenges that require knowledge, truth, and action.

Crown-rump length measurement error: impact on assessment of growth.

OBJECTIVE: To examine the impact of first-trimester crown-rump length (CRL) measurement error on the interpretation of estimated fetal weight (EFW) and classification of fetuses as small-, large- or appropriate-for-gestational age on subsequent growth scans. METHODS: We examined the effects of errors of ± 2, ± 3 and ± 4 mm in the measurement of fetal CRL on percentiles of EFW at 20, 32 and 36 weeks' gestation and classification as small-, large- or appropriate-for-gestational age. Published data on CRL measurement error were used to determine variation present in practice. RESULTS: A measurement error of -2 mm in first-trimester CRL shifts an EFW on the 10th percentile at the 20-week scan to around the 20th percentile, and the effect of a CRL measurement error of + 2 mm would shift an EFW on the 10th percentile to around the 5th percentile. At 32 weeks, a first-trimester CRL measurement error would shift an EFW on the 10th percentile to the 7th (+ 2 mm) or 14th (-2 mm) percentile; at 36 weeks, the EFW would shift from the 10th percentile to the 8th (+ 2 mm) or 12th (-2 mm) percentile. Published data suggest that measurement errors of 2 mm or more are common in practice. CONCLUSION: Because of the widespread and potentially severe consequences of CRL measurement errors as small as 2 mm on clinical assessment, patient management and research results, there is a need to increase awareness of the impact of CRL measurement error and to reduce measurement error variation through standardization and quality control. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Report on G4-Med, a Geant4 benchmarking system for medical physics applications developed by the Geant4 Medical Simulation Benchmarking Group.

BACKGROUND: Geant4 is a Monte Carlo code extensively used in medical physics for a wide range of applications, such as dosimetry, micro- and nanodosimetry, imaging, radiation protection, and nuclear medicine. Geant4 is continuously evolving, so it is crucial to have a system that benchmarks this Monte Carlo code for medical physics against reference data and to perform regression testing. AIMS: To respond to these needs, we developed G4-Med, a benchmarking and regression testing system of Geant4 for medical physics. MATERIALS AND METHODS: G4-Med currently includes 18 tests. They range from the benchmarking of fundamental physics quantities to the testing of Monte Carlo simulation setups typical of medical physics applications. Both electromagnetic and hadronic physics processes and models within the prebuilt Geant4 physics lists are tested. The tests included in G4-Med are executed on the CERN computing infrastructure via the use of the geant-val web application, developed at CERN for Geant4 testing. The physical observables can be compared to reference data for benchmarking and to results of previous Geant4 versions for regression testing purposes. RESULTS: This paper describes the tests included in G4-Med and shows the results derived from the benchmarking of Geant4 10.5 against reference data. DISCUSSION: Our results indicate that the Geant4 electromagnetic physics constructor G4EmStandardPhysics_option4 gives a good agreement with the reference data for all the tests. The QGSP_BIC_HP physics list provided an overall adequate description of the physics involved in hadron therapy, including proton and carbon ion therapy. New tests should be included in the next stage of the project to extend the benchmarking to other physical quantities and application scenarios of interest for medical physics. CONCLUSION: The results presented and discussed in this paper will aid users in tailoring physics lists to their particular application.

Preliminary results in using Deep Learning to emulate BLOB, a nuclear interaction model.

PURPOSE: A reliable model to simulate nuclear interactions is fundamental for Ion-therapy. We already showed how BLOB ("Boltzmann-Langevin One Body"), a model developed to simulate heavy ion interactions up to few hundreds of MeV/u, could simulate also 12C reactions in the same energy domain. However, its computation time is too long for any medical application. For this reason we present the possibility of emulating it with a Deep Learning algorithm. METHODS: The BLOB final state is a Probability Density Function (PDF) of finding a nucleon in a position of the phase space. We discretised this PDF and trained a Variational Auto-Encoder (VAE) to reproduce such a discrete PDF. As a proof of concept, we developed and trained a VAE to emulate BLOB in simulating the interactions of 12C with 12C at 62 MeV/u. To have more control on the generation, we forced the VAE latent space to be organised with respect to the impact parameter (b) training a classifier of b jointly with the VAE. RESULTS: The distributions obtained from the VAE are similar to the input ones and the computation time needed to use the VAE as a generator is negligible. CONCLUSIONS: We show that it is possible to use a Deep Learning approach to emulate a model developed to simulate nuclear reactions in the energy range of interest for Ion-therapy. We foresee the implementation of the generation part in C++ and to interface it with the most used Monte Carlo toolkit: Geant4.

Impact of biometric measurement error on identification of small- and large-for-gestational-age fetuses.

OBJECTIVES: First, to obtain measurement-error models for biometric measurements of fetal abdominal circumference (AC), head circumference (HC) and femur length (FL), and, second, to examine the impact of biometric measurement error on sonographic estimated fetal weight (EFW) and its effect on the prediction of small- (SGA) and large- (LGA) for-gestational-age fetuses with EFW < 10th and > 90th percentile, respectively. METHODS: Measurement error standard deviations for fetal AC, HC and FL were obtained from a previous large study on fetal biometry utilizing a standardized measurement protocol and both qualitative and quantitative quality-control monitoring. Typical combinations of AC, HC and FL that gave EFW on the 10th and 90th percentiles were determined. A Monte-Carlo simulation study was carried out to examine the effect of measurement error on the classification of fetuses as having EFW above or below the 10th and 90th percentiles. RESULTS: Errors were assumed to follow a Gaussian distribution with a mean of 0 mm and SDs, obtained from a previous well-conducted study, of 6.93 mm for AC, 5.15 mm for HC and 1.38 mm for FL. Assuming errors according to such distributions, when the 10th and 90th percentiles are used to screen for SGA and LGA fetuses, respectively, the detection rates would be 78.0% at false-positive rates of 4.7%. If the cut-offs were relaxed to the 30th and 70th percentiles, the detection rates would increase to 98.2%, but at false-positive rates of 24.2%. Assuming half of the spread in the error distribution, using the 10th and 90th percentiles to screen for SGA and LGA fetuses, respectively, the detection rates would be 86.6% at false-positive rates of 2.3%. If the cut-offs were relaxed to the 15th and 85th percentiles, respectively, the detection rates would increase to 97.0% and the false-positive rates would increase to 6.3%. CONCLUSIONS: Measurement error in fetal biometry causes substantial error in EFW, resulting in misclassification of SGA and LGA fetuses. The extent to which improvement can be achieved through effective quality assurance remains to be seen but, as a first step, it is important for practitioners to understand how biometric measurement error impacts the prediction of SGA and LGA fetuses. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Preliminary results coupling "Stochastic Mean Field" and "Boltzmann-Langevin One Body" models with Geant4.

PURPOSE: Monte Carlo (MC) simulations are widely used for medical applications and nuclear reaction models are fundamental for the simulation of the particle interactions with patients in ion therapy. Therefore, it is of utmost importance to have reliable models in MC simulations for such interactions. Geant4 is one of the most used toolkits for MC simulation. However, its models showed severe limitations in reproducing the yields measured in the interaction of ion beams below 100 MeV/u with thin targets. For this reason, we interfaced two models, SMF ("Stochastic Mean Field") and BLOB ("Boltzmann-Langevin One Body"), dedicated to simulate such reactions, with Geant4. METHODS: Both SMF and BLOB are semi-classical, one-body approaches to solve the Boltzmann-Langevin equation. They include an identical treatment of the mean-field propagation, on the basis of the same effective interaction, but they differ in the way fluctuations are included. Furthermore, we tested a correction to the excitation energy calculated for the light fragments emerging from the simulations and a simple coalescence model. RESULTS: While both SMF and BLOB have been developed to simulate heavy ion interactions, they show very good results in reproducing the experimental yields of light fragments, up to alpha particles, obtained in the interaction of 12C with a thin carbon target at 62 MeV/u. CONCLUSIONS: BLOB in particular gives promising results and this stresses the importance of integrating it into the Geant4 toolkit.

Chromosome microarray proficiency testing and analysis of quality metric data trends through an external quality assessment program for Australasian laboratories.

Chromosome microarrays are an essential tool for investigation of copy number changes in children with congenital anomalies and intellectual deficit. Attempts to standardise microarray testing have focused on establishing technical and clinical quality criteria, however external quality assessment programs are still needed. We report on a microarray proficiency testing program for Australasian laboratories. Quality metrics evaluated included analytical accuracy, result interpretation, report completeness, and laboratory performance data: sample numbers, success and abnormality rate and reporting times. Between 2009 and 2014 nine samples were dispatched with variable results for analytical accuracy (30-100%), correct interpretation (32-96%), and report completeness (30-92%). Laboratory performance data (2007-2014) showed an overall mean success rate of 99.2% and abnormality rate of 23.6%. Reporting times decreased from >90 days to <30 days for normal results and from >102 days to <35 days for abnormal results. Data trends showed a positive correlation with improvement for all these quality metrics, however only 'report completeness' and reporting times reached statistical significance. Whether the overall improvement in laboratory performance was due to participation in this program, or from accumulated laboratory experience over time, is not clear. Either way, the outcome is likely to assist referring clinicians and improve patient care.

Improving access to dental care for vulnerable children; further development of the Back2School programme in 2013.

This paper describes a service evaluation of a dental treatment programme providing care to children not normally taken to the dentist. It explains the extension of the Back2School programme from the pilot phase and assesses if a mobile dental unit (MDU) can provide a high quality service. The public health competencies it illustrates include oral health improvement, developing and monitoring quality dental services, and collaborative working.

Serum free ß-human chorionic gonadotropin in the three trimesters of pregnancy: effects of maternal characteristics and medical history.

OBJECTIVE: To define the contribution of maternal variables which influence the measured level of maternal serum free ß-human chorionic gonadotropin (ß-hCG) in screening for pregnancy complications. METHODS: Maternal characteristics and medical history were recorded and serum free ß-hCG was measured in women with a singleton pregnancy attending for three routine hospital visits at 11 + 0 to 13 + 6, 19 + 0 to 24 + 6 and 30 + 0 to 34 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths ≥ 24 weeks' gestation, variables from maternal demographic characteristics and medical history that are important in the prediction of free ß-hCG were determined from a linear mixed-effects multiple regression. RESULTS: Serum free ß-hCG was measured in 94 985 cases in the first trimester, 7879 in the second trimester and 8424 in the third trimester. Significant independent contributions to serum free ß-hCG were provided by gestational age, maternal weight, age and racial origin, cigarette smoking, method of conception, diabetes mellitus and family history of pre-eclampsia (PE) in the mother of the patient. The effects of some variables were similar and those for others differed in each trimester. Random-effects multiple regression analysis was used to define the contribution of maternal variables that influence the measured level of serum free ß-hCG and express the values as multiples of the median (MoMs). The model was shown to provide an adequate fit of MoM values for all covariates both in pregnancies that developed PE and in those without this pregnancy complication. CONCLUSIONS: A model was fitted to express measured serum free ß-hCG across the three trimesters of pregnancy as MoMs after adjusting for variables from maternal characteristics and medical history that affect this measurement.

Serum pregnancy-associated plasma protein-A in the three trimesters of pregnancy: effects of maternal characteristics and medical history.

OBJECTIVE: To define the contribution of maternal variables which influence the measured level of maternal serum pregnancy-associated plasma protein-A (PAPP-A) in screening for pregnancy complications. METHODS: Maternal characteristics and medical history were recorded and serum PAPP-A was measured in women with a singleton pregnancy attending for three routine hospital visits at 11 + 0 to 13 + 6, 19 + 0 to 24 + 6 and 30 + 0 to 34 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths ≥ 24 weeks' gestation, variables from maternal demographic characteristics and medical history that are important in the prediction of PAPP-A were determined from a linear mixed-effects multiple regression. RESULTS: Serum PAPP-A was measured in 94,966 cases in the first trimester, 7785 in the second trimester and 8286 in the third trimester. Significant independent contributions to serum PAPP-A were provided by gestational age, maternal weight, height, racial origin, cigarette smoking, diabetes mellitus, method of conception, previous pregnancy with or without pre-eclampsia (PE) and birth-weight Z-score of the neonate in the previous pregnancy. The effects of some variables were similar and those for others differed in the three different trimesters. Random-effects multiple regression analysis was used to define the contribution of maternal variables that influence the measured level of serum PAPP-A and express the values as multiples of the median (MoMs). The model was shown to provide an adequate fit of MoM values for all covariates, both in pregnancies that developed PE and in those without this pregnancy complication. CONCLUSIONS: A model was fitted to express the measured serum PAPP-A across the three trimesters of pregnancy as MoMs, after adjusting for variables from maternal characteristics and medical history that affect this measurement.

A cohort study of influences, health outcomes and costs of patients' health-seeking behaviour for minor ailments from primary and emergency care settings.

OBJECTIVES: To compare health-related and cost-related outcomes of consultations for symptoms suggestive of minor ailments in emergency departments (EDs), general practices and community pharmacies. DESIGN: Observational study; prospective cohort design. SETTING: EDs (n=2), general practices (n=6) and community pharmacies (n=10) in a mix of rural/urban and deprived/affluent areas across North East Scotland and East Anglia. Participants Adults (≥18 years) presenting between 09:00 and 18:00 (Monday-Friday) in general practices and 09:00-18:00 (Monday-Saturday) in pharmacies and EDs with ≥1 of the following: musculoskeletal pain; eye discomfort; gastrointestinal disturbance; or upper respiratory tract-related symptoms. INTERVENTIONS: Participants completed three questionnaires: baseline (prior to index consultation); satisfaction with index consultation and follow-up (2 weeks after index consultation). MAIN OUTCOME MEASURES: Symptom resolution, quality of life, costs, satisfaction and influences on care-seeking behaviour. RESULTS: 377 patients participated, recruited from EDs (81), general practices (162) and community pharmacies (134). The 2-week response rate was 70% (264/377). Symptom resolution was similar across all three settings: ED (37.3%), general practice (35.7%) and pharmacy (44.3%). Mean overall costs per consultation were significantly lower for pharmacy (£29.30 (95% CI £21.60 to £37.00)) compared with general practice (£82.34 (95% CI £63.10 to £101.58)) and ED (£147.09 (95% CI £125.32 to £168.85)). Satisfaction varied across settings and by measure used. Compared with pharmacy and general practice use, ED use was significantly (p<0.001) associated with first episode and short duration of symptom(s), as well as higher levels of perceived seriousness and urgency for seeking care. Convenience of location was the most common reason for choice of consultation setting. CONCLUSIONS: These results suggest similar health-related outcomes and substantially lower costs with pharmacy consultations for minor ailments. Effective strategies are now needed to shift demand for minor ailment management away from EDs and general practices to the community pharmacy setting.

Serum alpha-fetoprotein in the three trimesters of pregnancy: effects of maternal characteristics and medical history.

OBJECTIVE: To define the contribution of maternal variables which influence the measured level of maternal serum alpha-fetoprotein (AFP) in screening for pregnancy complications. METHODS: Maternal characteristics and medical history were recorded and serum AFP was measured in women with a singleton pregnancy attending for three routine hospital visits at 11 + 0 to 13 + 6, 19 + 0 to 24 + 6 and 30 + 0 to 34 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths ≥ 24 weeks' gestation, variables from maternal demographic characteristics and medical history that are important in the prediction of AFP were determined from a linear mixed-effects multiple regression. RESULTS: Serum AFP was measured in 17 071 cases in the first trimester, 8583 in the second trimester and 8607 in the third trimester. Significant independent contributions to serum AFP were provided by gestational age, maternal weight, racial origin, gestational age at delivery and birth-weight Z-score of the neonate of the previous pregnancy and interpregnancy interval. Cigarette smoking was found to significantly affect serum AFP in the first trimester only. The machine used to measure serum AFP was also found to have a significant effect. Random-effects multiple regression analysis was used to define the contribution of maternal variables that influence the measured level of serum AFP and express the values as multiples of the median (MoMs). The model was shown to provide an adequate fit of MoM values for all covariates, both in pregnancies that developed pre-eclampsia and in those without this pregnancy complication. CONCLUSIONS: A model was fitted to express measured serum AFP across the three trimesters of pregnancy as MoMs, after adjusting for variables from maternal characteristics and medical history that affect this measurement.

Uterine artery pulsatility index in the three trimesters of pregnancy: effects of maternal characteristics and medical history.

OBJECTIVE: To define the contribution of maternal variables that influence the measured uterine artery pulsatility index (UtA-PI) in screening for pregnancy complications. METHODS: Maternal characteristics and medical history were recorded, and UtA-PI was measured, in women with a singleton pregnancy attending for three routine hospital visits at 11 + 0 to 13 + 6 weeks, 19 + 0 to 24 + 6 weeks and 30 + 0 to 34 + 6 weeks or 35 + 0 to 37 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths at ≥ 24 weeks' gestation, variables from maternal demographic characteristics and medical history that are important in the prediction of UtA-PI were determined from linear mixed-effects multiple regression. RESULTS: UtA-PI was measured in 90 484 cases in the first trimester, 66 862 cases in the second trimester and 33 470 cases in the third trimester of pregnancy. Significant independent contributions to UtA-PI were provided by gestational age, maternal age, weight, racial origin and a history of pre-eclampsia (PE) in the previous pregnancy. Random-effects multiple regression analysis was used to define the contribution of maternal variables that influence the measured UtA-PI and express the values as multiples of the median (MoM). The model was shown to provide an adequate fit of MoM values for all covariates both in pregnancies that developed PE and in those that did not. CONCLUSIONS: A model was fitted to express the measured UtA-PI as MoMs after adjustment for variables from maternal characteristics and medical history that affect this measurement.

A unified approach to risk assessment for fetal aneuploidies.

OBJECTIVE: To examine the potential impact of combining measures from cell-free DNA (cfDNA) testing with maternal age and first-trimester biomarkers in screening for fetal trisomies. METHODS: This was a theoretical study using Bayes' theorem to combine the a priori risk for fetal trisomy 21 derived from maternal age with likelihoods from nuchal translucency thickness, serum pregnancy-associated plasma protein-A, serum free ß-human chorionic gonadotropin and plasma cfDNA. We adopted a binomial counting model for the cfDNA likelihoods and developed a model to account for errors in estimating fetal fraction. RESULTS: When Bayes' theorem was used to combine the a priori risk for trisomy 21 derived from the first-trimester combined test with likelihoods from the cfDNA test, and when the true fetal fraction was known, the detection rate increased from 62% at a fetal fraction of 4% to 100% at a fetal fraction of ≥ 9%; the positive likelihood ratio (trisomic/euploid) increased from 620 to 1000 and the negative likelihood ratio (euploid/trisomic) increased from 3 to > 10 000. When the fetal fraction is < 4%, the cfDNA test has traditionally been considered to be a failure, but the cfDNA results can be used to improve the performance of screening by the combined test. CONCLUSIONS: In contingent policies that use the first-trimester combined test for first-line screening to select the subgroup for cfDNA testing, the data from the latter should be used to update the risk from the former. Individual patient results from cfDNA testing depend crucially on the fetal fraction and the precision of its measurement.

Rationale and study design of the REM-HF study: remote management of heart failure using implanted devices and formalized follow-up procedures.

AIMS: We wish to assess the clinical and cost-effectiveness of remote monitoring of heart failure patients with cardiac implanted electronic devices. METHODS: REM-HF is a multicentre, randomized, non-blinded, parallel trial designed to compare weekly remote monitoring-driven management with usual care for patients with cardiac implanted electronic devices (ICD, CRT-D, or CRT-P). The trial is event driven, and the final analysis will be performed when 546 events have been observed or the study is terminated at the interim analysis. We have randomized 1650 patients to be followed up for a minimum of 2 years. Patients will remain in the trial up to study termination. The first patient was randomized in September 2011 and the study is expected to complete in early 2016. The primary combined endpoint is time to first event of all-cause death or unplanned hospitalization for cardiovascular reasons. An economic evaluation will be performed, estimating the cost per quality-adjusted life year, with direct costs estimated from the National Health Service perspective and quality of life assessed by the EQ-5D, Short-Form 12, and Kansas City Cardiomyopathy Questionnaires. The study design has been informed by a feasibility study. CONCLUSION: REM-HF is a multicentre randomized study that will provide important data on the effect of remote monitoring-driven management of implanted cardiac devices on morbidity and mortality, as well as the cost-effectiveness of this approach.

The clinical relevance and newsworthiness of NIHR HTA-funded research: a cohort study.

OBJECTIVE: To assess the clinical relevance and newsworthiness of the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme funded reports. STUDY DESIGN: Retrospective cohort study. SETTING: The cohort included 311 NIHR HTA Programme funded reports publishing in HTA in the period 1 January 2007-31 December 2012. The McMaster Online Rating of Evidence (MORE) system independently identified the clinical relevance and newsworthiness of NIHR HTA publications and non-NIHR HTA publications. The MORE system involves over 4000 physicians rating publications on a scale of relevance (the extent to which articles are relevant to practice) and a scale of newsworthiness (the extent to which articles contain news or something clinicians are unlikely to know). MAIN OUTCOME MEASURES: The proportion of reports published in HTA meeting MORE inclusion criteria and mean average relevance and newsworthiness ratings were calculated and compared with publications from the same studies publishing outside HTA and non-NIHR HTA funded publications. RESULTS: 286/311 (92.0%) of NIHR HTA reports were assessed by MORE, of which 192 (67.1%) passed MORE criteria. The average clinical relevance rating for NIHR HTA reports was 5.48, statistically higher than the 5.32 rating for non-NIHR HTA publications (mean difference=0.16, 95% CI 0.04 to 0.29, p=0.01). Average newsworthiness ratings were similar between NIHR HTA reports and non-NIHR HTA publications (4.75 and 4.70, respectively; mean difference=0.05, 95% CI -0.18 to 0.07, p=0.402). NIHR HTA-funded original research reports were statistically higher for newsworthiness than reviews (5.05 compared with 4.64) (mean difference=0.41, 95% CI 0.18 to 0.64, p=0.001). CONCLUSIONS: Funding research of clinical relevance is important in maximising the value of research investment. The NIHR HTA Programme is successful in funding projects that generate outputs of clinical relevance.

A comparative assessment of waste incinerators in the UK.

The uptake in Europe of Energy from Waste (EfW) incinerator plants has increased rapidly in recent years. In the UK, 25 municipal waste incinerators with energy recovery are now in operation; however, their waste supply chains and business practices vary significantly. With over a hundred more plant developments being considered it is important to establish best business practices for ensuring efficient environmental and operational performance. By reviewing the 25 plants we identify four suitable case study plants to compare technologies (moving grate, fluidised bed and rotary kiln), plant economics and operations. Using data collected from annual reports and through interviews and site visits we provide recommendations for improving the supply chain for waste incinerators and highlight the current issues and challenges faced by the industry. We find that plants using moving grate have a high availability of 87-92%. However, compared to the fluidised bed and rotary kiln, quantities of bottom ash and emissions of hydrogen chloride and carbon monoxide are high. The uptake of integrated recycling practices, combined heat and power, and post incineration non-ferrous metal collections needs to be increased among EfW incinerators in the UK. We conclude that one of the major difficulties encountered by waste facilities is the appropriate selection of technology, capacity, site, waste suppliers and heat consumers. This study will be of particular value to EfW plant developers, government authorities and researchers working within the sector of waste management.

Care home managers' views of dental services for older people living in nursing and residential homes in inner city London.

OBJECTIVE: To investigate care home managers' views on the provision of dental care (current and future; urgent, check-up and follow-up) for their residents, barriers to care and the impact of policy changes, by type of home (nursing vs residential), with a view to informing the planning and provision of care. BASIC RESEARCH DESIGN: A cross sectional postal questionnaire survey and follow-up semi-structured interviews. SETTING: Care homes in South East London. PARTCIPANTS: All care home managers in three south east London boroughs. RESULTS: A 72% response rate (n=152) was achieved, 140 of which were designated as nursing and/or residential homes (92%). Almost all managers reported that the care homes had arrangements in place for residents to access some elements of dental care (99%, n=148). Reported barriers to care included residents' fear of treatment (53%), patients' limited mobility (45%) and waiting times for services (42%). Limited mobility (p=0.01) and transport issues (p=0.01) were more significant barriers for nursing homes, whereas fear (p=0.02) was more significant for residential homes. Access to a range of dental services and modes of service delivery were requested for the future; most notable were the demands for domiciliary services to be available to nursing homes and for residential homes to access local general dental practitioners to meet the needs of their residents. CONCLUSIONS: Managers report having arrangements in place for residents to access dental services; however, there was a clear view that future arrangements should be more appropriate to the needs and vulnerabilities of their residents.