Patient information leaflets (PILs) for UK randomised controlled trials : a feasibility study exploring whether they contain information to support decision making about trial participation

Peer reviewedPublisher PD

Associations of Body Mass and Fat Indexes With Cardiometabolic Traits

Background Body mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear. Objectives The aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits. Duration of exposure to and change in each index across adolescence were examined in relation to detailed traits in young adulthood. Methods BMI was examined alongside total, trunk, arm, and leg fat indexes (each in kilograms per square meter) from dual-energy x-ray absorptiometry at ages 10 and 18 years in relation to 230 traits from targeted metabolomics at age 18 years in 2,840 offspring from the Avon Longitudinal Study of Parents and Children. Results Higher total fat mass index and BMI at age 10 years were similarly associated with cardiometabolic traits at age 18 years, including higher systolic and diastolic blood pressure, higher very low-density lipoprotein and low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, higher triglycerides, and higher insulin and glycoprotein acetyls. Associations were stronger for both indexes measured at age 18 years and for gains in each index from age 10 to 18 years (e.g., 0.45 SDs [95% confidence interval: 0.38 to 0.53] in glycoprotein acetyls per SD unit gain in fat mass index vs. 0.38 SDs [95% confidence interval: 0.27 to 0.48] per SD unit gain in BMI). Associations resembled those for trunk fat index. Higher lean mass index was weakly associated with traits and was not protective against higher fat mass index. Conclusions The results of this study support abdominal fatness as a primary driver of cardiometabolic dysfunction and BMI as a useful tool for detecting its effects

Minimal change in structural, functional and inflammatory markers of lung disease in newborn screened infants with cystic fibrosis at one year

BACKGROUND: With the widespread introduction of newborn screening for cystic fibrosis (CF), there has been considerable emphasis on the need to develop objective markers of lung health that can be used during infancy. We hypothesised that in a newborn screened (NBS) UK cohort, evidence of airway inflammation and infection at one year would be associated with adverse structural and functional outcomes at the same age. METHODS: Infants underwent lung function testing, chest CT scan and bronchoscopy with bronchoalveolar lavage (BAL) at 1 year of age when clinically well. Microbiology cultures were also available from routine cough swabs. RESULTS: 65 infants had lung function, CT and BAL. Mean (SD) lung clearance index and forced expiratory volume in 0.5 s z-scores were 0.9(1.2) and -0.6(1.1) respectively; median Brody II CF-CT air trapping score on chest CT =0 (interquartile range 0-1, maximum possible score 27). Infants isolating any significant pathogen by 1 yr of age had higher LCI z-score (mean difference 0.9; 95%CI:0.4-1.4; p = 0.001) and a trend towards higher air trapping scores on CT (p = 0.06). BAL neutrophil elastase was detectable in 23% (10/43) infants in whom BAL supernatant was available. This did not relate to air trapping score on CT. CONCLUSIONS: In this UK NBS cohort at one year of age, lung and airway damage is much milder and associations between inflammation, abnormal physiology and structural changes were at best weak, contrary to our hypothesis and previously published reports. Continued follow-up will clarify longer term implications of these very mild structural, functional and inflammatory changes

Minimally invasive autopsy for fetuses and children based on a combination of post-mortem MRI and endoscopic examination: a feasibility study

BACKGROUND: Less invasive perinatal and paediatric autopsy methods, such as imaging alongside targeted endoscopy and organ biopsy, may address declining consent rates for traditional autopsy, but their acceptability and accuracy are not known. OBJECTIVES: The aims of this study were to provide empirical data on the acceptability and likely uptake for different types of autopsy among key stakeholders (study 1); and to analyse existing autopsy data sources to provide estimates of the potential efficacy of less invasive autopsy (LIA) and its projected utility in clinical practice (study 2). REVIEW METHODS: Study 1: this was a mixed-methods study. Parents were involved in research design and interpretation of findings. Substudy 1: a cross-sectional survey of 859 parents who had experienced miscarriage, termination of pregnancy for fetal anomaly, stillbirth, infant or child death, and interviews with 20 responders. Substudy 2: interviews with 25 health professionals and four coroners. Substudy 3: interviews with 16 religious leaders and eight focus groups, with 76 members of the Muslim and Jewish community. Study 2: a retrospective analysis of national data in addition to detailed information from an existing in-house autopsy database of > 5000 clinical cases that had undergone standard autopsy to determine the proportion of cases by clinical indication group for which tissue sampling of specific internal organs significantly contributed to the diagnosis. RESULTS: Substudy 1: 91% of participants indicated that they would consent to some form of LIA, 54% would consent to standard autopsy, 74% to minimally invasive autopsy (MIA) and 77% to non-invasive autopsy (NIA). Substudy 2: participants viewed LIA as a positive development, but had concerns around the limitations of the technology and de-skilling the workforce. Cost implications, skills and training requirements were identified as implementation challenges. Substudy 3: religious leaders agreed that NIA was religiously permissible, but MIA was considered less acceptable. Community members indicated that they might consent to NIA if the body could be returned for burial within 24 hours. Study 2: in 5-10% of cases of sudden unexplained death in childhood and sudden unexplained death in infants, the final cause of death is determined by routine histological sampling of macroscopically normal organs, predominantly the heart and lungs, and in this group routine histological sampling therefore remains an important aspect of investigation. In contrast, routine histological examination of macroscopically normal organs rarely (< 0.5%) provides the cause of death in fetal cases, making LIA and NIA approaches potentially highly applicable. LIMITATIONS: A key limitation of the empirical research is that it is hypothetical. Further research is required to determine actual uptake. Furthermore, because of the retrospective nature of the autopsy data set, findings regarding the likely contribution of organ sampling to final diagnosis are based on extrapolation of findings from historical autopsies, and prospective data collection is required to validate the conclusions. CONCLUSIONS: LIA is viable and acceptable (except for unexplained deaths), and likely to increase uptake. Further health economic, performance and implementation studies are required to determine the optimal service configuration required to offer this as routine clinical care. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Twin pregnancy with complete hydatidiform mole and coexisting fetus following ovulation induction with a non-prescribed clomiphene citrate regimen: a case report

<p>Abstract</p> <p>Introduction</p> <p>Twin pregnancy with complete hydatidiform mole represents a very rare obstetric problem. Management of such cases is always problematic because the possibility of fetal survival should always be weighed against the risk of complications of molar pregnancy.</p> <p>Case presentation</p> <p>A 34-year-old Caucasian woman presented to our center with mild vaginal bleeding. Our patient was 16 weeks pregnant after a seven-year period of primary infertility. She became pregnant following a non-prescribed regimen of clomiphene citrate extending from the second day to the 13th day of her last cycle. A transabdominal ultrasound examination revealed a twin pregnancy with complete hydatidiform mole and a coexisting fetus. Serum β human chorionic gonadotropin was falsely low as identified by serial dilution of the sample (the 'hook effect'). Our patient refused termination of pregnancy and she was hospitalized for strict observation and follow-up. Unfortunately, she developed an attack of severe vaginal bleeding and a hysterotomy was performed. The fetus died shortly after birth.</p> <p>Conclusions</p> <p>Twin pregnancy with complete hydatidiform mole represents a matter of controversy. We suggest that conservation should always be considered whenever tertiary care services and strict observation are available.</p

Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice

Hyperpolarizing GABAAR currents, the unitary events that underlie synaptic inhibition, are dependent upon efficient Cl− extrusion, a process that is facilitated by the neuronal specific K+/Cl− co-transporter KCC2. Its activity is also a determinant of the anticonvulsant efficacy of the canonical GABAAR-positive allosteric: benzodiazepines (BDZs). Compromised KCC2 activity is implicated in the pathophysiology of status epilepticus (SE), a medical emergency that rapidly becomes refractory to BDZ (BDZ-RSE). Here, we have identified small molecules that directly bind to and activate KCC2, which leads to reduced neuronal Cl− accumulation and excitability. KCC2 activation does not induce any overt effects on behavior but prevents the development of and terminates ongoing BDZ-RSE. In addition, KCC2 activation reduces neuronal cell death following BDZ-RSE. Collectively, these findings demonstrate that KCC2 activation is a promising strategy to terminate BDZ-resistant seizures and limit the associated neuronal injury

Chest radiographs versus CT for the detection of rib fractures in children (DRIFT): a diagnostic accuracy observational study

BACKGROUND: Internationally, chest radiography is the standard investigation for identifying rib fractures in suspected physical abuse in infants. Several small observation studies in children have found that chest CT can provide greater accuracy than radiography for fracture detection, potentially aiding medicolegal proceedings in abuse cases; however, to our knowledge, this greater accuracy has not been comprehensively evaluated. We aimed to determine differences in rib fracture detection rates between post-mortem chest radiographs and chest CT images, using forensic autopsy as the reference standard. METHODS: In this retrospective diagnostic accuracy study, we searched the Great Ormond Street Hospital (London, UK) radiology information system for all children aged 0-16 years who had a post-mortem skeletal survey (ie, full-body radiography), CT, and full autopsy between Jan 1, 2012, and Jan 1, 2017, for a purpose of death investigation. Cases were excluded if the imaging was done for a reason other than a forensic investigation or if image quality was suboptimal. Radiologists were recruited as reporters on a voluntary basis via membership databases from international radiology and post-mortem imaging societies with no specific inclusion or exclusion criteria. Reporters were sent a set of chest radiographs on a password protected and encrypted USB flash drive or via a secure filesharing website and independently reported on the presence of rib fractures, fracture location, and the confidence level of their interpretation. They were masked to the clinical information of the images. 1 month later, the same reporters were sent CTs for the same cases in a random order and asked to report on the same features. The primary objective was to compare the accuracy of detection of rib fractures by use of post-mortem chest radiographs and CTs, with autopsy data as reference standard. Accuracy was assessed by comparison of diagnostic statistics, calculated using random-intercept multilevel logistic models with reporter and patient included as cross-classified random-effects. FINDINGS: 25 cases of children (aged 1 month to 7 years), with 136 rib fractures at autopsy with paired post-mortem chest radiographs and CTs, were selected for analysis. 38 radiologists were recruited as reporters from 23 international centres; 12 (32%) were consultants, median experience of 14·5 years (range 6-27), and 26 (68%) were registrars, median experience of 4 years (range 2-9). Across all radiologists, three times as many rib fractures were correctly detected by use of chest CTs compared with chest radiography (sensitivity 44·9% [95% CI 31·7-58·9] vs 13·5% [8·1-21·5]; difference 31·4% [23·3-37·8; p<0·001]). Sensitivity for detection on the correct rib was higher by use of CT than by use of radiography (62·4% [95% CI 44·9-77·1] vs 23·1% [12·9-37·8]; difference 39·3% [31·9-42·2; p<0·001]), as was diagnosis of a patient with any rib fracture or fractures (81·5% [75·8-86·0] vs 64·7% [57·3-71·4]; difference 16·7% [11·5-22·2; p<0·001]). Radiologist confidence was higher when using CT images than radiographs (highest confidence rating given on 3317 [63·6%] of 5218 fractures for CT vs 1518 [46·6%] of 3303 on radiographs) and was a predictor for accurate fracture detection. INTERPRETATION: Chest CT provides greater accuracy than conventional chest radiography for post-mortem rib fracture detection, irrespective of radiologist experience or fracture location, although both methods detected a substantial number of false positives. The diagnostic accuracy of CT should be studied further in live children ideally in a multicentre trial to assess the applicability of our results. FUNDING: Great Ormond Street Children's Charity, Medical Research Council, Royal College of Radiologists, Research Councils UK, National Institute for Health Research