Fetal exome sequencing for isolated increased nuchal translucency: should we be doing it?

Objective: To evaluate the utility of prenatal exome sequencing (ES) for isolated increased nuchal translucency (NT) and investigate factors which increase diagnostic yield. Design: Retrospective analysis of data from two prospective cohort studies. Setting: Fetal medicine centres in the UK and USA. Population: Fetuses with increased NT ≥3.5mm at 11-14 weeks’ gestation recruited to the Prenatal Assessment of Genomes and Exomes (PAGE) and Columbia fetal WES studies (n = 213). Methods: We grouped cases based on (i) the presence of additional structural abnormalities at presentation in the first trimester or later in pregnancy, and (ii) NT measurement at presentation. We compared diagnostic rates between groups using Fisher exact test. Main Outcome Measures: Detection of diagnostic genetic variants considered to have caused the observed fetal structural anomaly. Results: Diagnostic variants were detected in 12 (22.2%) of 54 fetuses presenting with non-isolated increased NT, 12 (32.4%) of 37 fetuses with isolated increased NT in the first trimester and additional abnormalities later in pregnancy, and 2 (1.8%) of 111 fetuses with isolated increased NT in the first trimester and no other abnormalities on subsequent scans. Diagnostic rate also increased with increasing size of NT. Conclusions: The diagnostic yield of prenatal ES is low for fetuses with isolated increased NT but significantly higher where there are additional structural anomalies. Prenatal ES may not be appropriate for truly isolated increased NT but timely, careful ultrasound scanning to identify other anomalies emerging later can direct testing to focus where there is a higher likelihood of diagnosis

Use of hierarchical models to evaluate performance of cardiac surgery centres in the Italian CABG outcome study

<p>Abstract</p> <p>Background</p> <p>Hierarchical modelling represents a statistical method used to analyze nested data, as those concerning patients afferent to different hospitals. Aim of this paper is to build a hierarchical regression model using data from the "Italian CABG outcome study" in order to evaluate the amount of differences in adjusted mortality rates attributable to differences between centres.</p> <p>Methods</p> <p>The study population consists of all adult patients undergoing an isolated CABG between 2002–2004 in the 64 participating cardiac surgery centres.</p> <p>A risk adjustment model was developed using a classical single-level regression. In the multilevel approach, the variable "clinical-centre" was employed as a group-level identifier. The intraclass correlation coefficient was used to estimate the proportion of variability in mortality between groups. Group-level residuals were adopted to evaluate the effect of clinical centre on mortality and to compare hospitals performance. Spearman correlation coefficient of ranks (<it>ρ</it>) was used to compare results from classical and hierarchical model.</p> <p>Results</p> <p>The study population was made of 34,310 subjects (mortality rate = 2.61%; range 0.33–7.63). The multilevel model estimated that 10.1% of total variability in mortality was explained by differences between centres. The analysis of group-level residuals highlighted 3 centres (VS 8 in the classical methodology) with estimated mortality rates lower than the mean and 11 centres (VS 7) with rates significantly higher. Results from the two methodologies were comparable (<it>ρ </it>= 0.99).</p> <p>Conclusion</p> <p>Despite known individual risk-factors were accounted for in the single-level model, the high variability explained by the variable "clinical-centre" states its importance in predicting 30-day mortality after CABG.</p

A novel isolator-based system promotes viability of human embryos during laboratory processing

In vitro fertilisation (IVF) and related technologies are arguably the most challenging of all cell culture applications. The starting material is a single cell from which one aims to produce an embryo capable of establishing a pregnancy eventually leading to a live birth. Laboratory processing during IVF treatment requires open manipulations of gametes and embryos, which typically involves exposure to ambient conditions. To reduce the risk of cellular stress, we have developed a totally enclosed system of interlinked isolator-based workstations designed to maintain oocytes and embryos in a physiological environment throughout the IVF process. Comparison of clinical and laboratory data before and after the introduction of the new system revealed that significantly more embryos developed to the blastocyst stage in the enclosed isolator-based system compared with conventional open-fronted laminar flow hoods. Moreover, blastocysts produced in the isolator-based system contained significantly more cells and their development was accelerated. Consistent with this, the introduction of the enclosed system was accompanied by a significant increase in the clinical pregnancy rate and in the proportion of embryos implanting following transfer to the uterus. The data indicate that protection from ambient conditions promotes improved development of human embryos. Importantly, we found that it was entirely feasible to conduct all IVF-related procedures in the isolator-based workstations

Predictability of evolutionary trajectories in fitness landscapes

Experimental studies on enzyme evolution show that only a small fraction of all possible mutation trajectories are accessible to evolution. However, these experiments deal with individual enzymes and explore a tiny part of the fitness landscape. We report an exhaustive analysis of fitness landscapes constructed with an off-lattice model of protein folding where fitness is equated with robustness to misfolding. This model mimics the essential features of the interactions between amino acids, is consistent with the key paradigms of protein folding and reproduces the universal distribution of evolutionary rates among orthologous proteins. We introduce mean path divergence as a quantitative measure of the degree to which the starting and ending points determine the path of evolution in fitness landscapes. Global measures of landscape roughness are good predictors of path divergence in all studied landscapes: the mean path divergence is greater in smooth landscapes than in rough ones. The model-derived and experimental landscapes are significantly smoother than random landscapes and resemble additive landscapes perturbed with moderate amounts of noise; thus, these landscapes are substantially robust to mutation. The model landscapes show a deficit of suboptimal peaks even compared with noisy additive landscapes with similar overall roughness. We suggest that smoothness and the substantial deficit of peaks in the fitness landscapes of protein evolution are fundamental consequences of the physics of protein folding.Comment: 14 pages, 7 figure

Profiling quality of care for patients with chronic headache in three different German hospitals – a case study

BACKGROUND: Legal requirements for quality assurance in German rehabilitation hospitals include comparisons of providers. Objective is to describe and to compare outcome quality of care offered by three hospitals providing in-patient rehabilitative treatment exemplified for patients with chronic headache. METHODS: We performed a prospective three center observational study on patients suffering from chronic headache. Patients underwent interventions commonly used according to internal guidelines of the hospitals. Measurements were taken at three points in time (at admission, at discharge and 6 months after discharge). Indicators of outcome quality included pain intensity and frequency of pain, functional ability, depression, quality of life and health related behavior. Analyses of differences amongst the hospitals were adjusted by covariates due to case-mix situation. RESULTS: 306 patients from 3 hospitals were included in statistical analysis. Amongst the hospitals, patients differed significantly in age, education, diagnostic subgroups, beliefs, and with respect to some pain-related baseline values (covariates). Patients in all three hospitals benefited from intervention to a clinically relevant degree. At discharge from hospital, outcome quality differed significantly after adjustment according to case-mix only in terms of patients' global assessment of treatment results. Six months after discharge, the only detectable significant differences were for secondary outcomes like improved coping with stress or increased use of self-help. The profiles for satisfaction with the hospital stay showed clear differences amongst patients. CONCLUSION: The results of this case study do not suggest a definite overall ranking of the three hospitals that were compared, but outcome profiles offer a multilayer platform of reliable information which might facilitate decision making

Access to specialist cancer care: is it equitable?

The first principle of the Calman–Hine report's recommendations on cancer services was that all patients should have access to a uniformly high quality of care wherever they may live. This study aimed to assess whether the uptake of chemotherapy for colorectal cancer varied by hospital type in Scotland. Hospitals were classified according to cancer specialisation rather than volume of patients. To indicate cancer specialisation, hospitals were classified as ‘cancer centres’, ‘cancer units’ and ‘non-cancer’ hospitals. Colorectal cancer cases were obtained from cancer registrations linked to hospital discharge data for the period January 1992 to December 1996. Multilevel logistic regression was used to model the binary outcome, namely whether or not a patient received chemotherapy within 6 months of first admission to any hospital. The results showed that patients admitted first to a ‘non-cancer’ hospital were less than half as likely to go on to receive chemotherapy as those first admitted to a cancer unit or centre (OR=0.28). This result was not explained by distance between hospital of first admission and nearest cancer centre, nor by increasing age or severity of illness. The study covers the period immediately preceding the introduction of the Calman–Hine report in Scotland and should serve as a baseline for future monitoring of access to specialist care

Positive selection in dNTPase SAMHD1 throughout mammalian evolution

The vertebrate protein SAMHD1 is highly unusual in having roles in cellular metabolic regulation, antiviral restriction, and regulation of innate immunity. Its deoxynucleoside triphosphohydrolase activity regulates cellular dNTP concentration, reducing levels below those required by lentiviruses and other viruses to replicate. To counter this threat, some primate lentiviruses encode accessory proteins that bind SAMHD1 and induce its degradation; in turn, positive diversifying selection has been observed in regions bound by these lentiviral proteins, suggesting that primate SAMHD1 has coevolved to evade these countermeasures. Moreover, deleterious polymorphisms in human SAMHD1 are associated with autoimmune disease linked to uncontrolled DNA synthesis of endogenous retroelements. Little is known about how evolutionary pressures affect these different SAMHD1 functions. Here, we examine the deeper history of these interactions by testing whether evolutionary signatures in SAMHD1 extend to other mammalian groups and exploring the molecular basis of this coevolution. Using codon-based likelihood models, we find positive selection in SAMHD1 within each mammal lineage for which sequence data are available. We observe positive selection at sites clustered around T592, a residue that is phosphorylated to regulate SAMHD1 activity. We verify experimentally that mutations within this cluster affect catalytic rate and lentiviral restriction, suggesting that virus-host coevolution has required adaptations of enzymatic function. Thus, persistent positive selection may have involved the adaptation of SAMHD1 regulation to balance antiviral, metabolic, and innate immunity functions

Fetal exome sequencing for isolated increased nuchal translucency: should we be doing it?

Funder: National Institute for Health Research (NIHR) Biomedical Research Centre, Great Ormond Street Hospital; Id: http://dx.doi.org/10.13039/501100019256OBJECTIVE: To evaluate the utility of prenatal exome sequencing (ES) for isolated increased nuchal translucency (NT) and to investigate factors that increase diagnostic yield. DESIGN: Retrospective analysis of data from two prospective cohort studies. SETTING: Fetal medicine centres in the UK and USA. POPULATION: Fetuses with increased NT ≥3.5 mm at 11-14 weeks of gestation recruited to the Prenatal Assessment of Genomes and Exomes (PAGE) and Columbia fetal whole exome sequencing studies (n = 213). METHODS: We grouped cases based on (1) the presence of additional structural abnormalities at presentation in the first trimester or later in pregnancy, and (2) NT measurement at presentation. We compared diagnostic rates between groups using Fisher exact test. MAIN OUTCOME MEASURES: Detection of diagnostic genetic variants considered to have caused the observed fetal structural anomaly. RESULTS: Diagnostic variants were detected in 12 (22.2%) of 54 fetuses presenting with non-isolated increased NT, 12 (32.4%) of 37 fetuses with isolated increased NT in the first trimester and additional abnormalities later in pregnancy, and 2 (1.8%) of 111 fetuses with isolated increased NT in the first trimester and no other abnormalities on subsequent scans. Diagnostic rate also increased with increasing size of NT. CONCLUSIONS: The diagnostic yield of prenatal ES is low for fetuses with isolated increased NT but significantly higher where there are additional structural anomalies. Prenatal ES may not be appropriate for truly isolated increased NT but timely, careful ultrasound scanning to identify other anomalies emerging later can direct testing to focus where there is a higher likelihood of diagnosis

A Secular Trend toward Earlier Male Sexual Maturity: Evidence from Shifting Ages of Male Young Adult Mortality

This paper shows new evidence of a steady long-term decline in age of male sexual maturity since at least the mid-eighteenth century. A method for measuring the timing of male maturity is developed based on the age at which male young adult mortality accelerates. The method is applied to mortality data from Sweden, Denmark, Norway, the United Kingdom, and Italy. The secular trend toward earlier male sexual maturity parallels the trend toward earlier menarche for females, suggesting that common environmental cues influence the speed of both males' and females' sexual maturation

Alvimopan for the Management of Postoperative Ileus After Bowel Resection: Characterization of Clinical Benefit by Pooled Responder Analysis

BACKGROUND: A pooled post hoc responder analysis was performed to assess the clinical benefit of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, for the management of postoperative ileus after bowel resection. METHODS: Adult patients who underwent laparotomy for bowel resection scheduled for opioid-based intravenous patient-controlled analgesia received oral alvimopan or placebo preoperatively and twice daily postoperatively until hospital discharge or for 7 postoperative days. The proportion of responders and numbers needed to treat (NNT) were examined on postoperative days (POD) 3-8 for GI-2 recovery (first bowel movement, toleration of solid food) and hospital discharge order (DCO) written. RESULTS: Alvimopan significantly increased the proportion of patients with GI-2 recovery and DCO written by each POD (P \u3c 0.001 for all). More patients who received alvimopan achieved GI-2 recovery on or before POD 5 (alvimopan, 80%; placebo, 66%) and DCO written before POD 7 (alvimopan, 87%; placebo, 72%), with corresponding NNTs equal to 7. CONCLUSIONS: On each POD analyzed, alvimopan significantly increased the proportion of patients who achieved GI-2 recovery and DCO written versus placebo and was associated with relatively low NNTs. The results of these analyses provide additional characterization and support for the overall clinical benefit of alvimopan in patients undergoing bowel resection